Embed Size (px)
Citation preview
G
A
R
AP
MQ1
M
a
ARR1AA
KDDMOP
C
PIaTs
1h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
ARTICLE IN PRESS Model
RR 489 1–8
Ageing Research Reviews xxx (2014) xxx– xxx
Contents lists available at ScienceDirect
Ageing Research Reviews
j ourna l h om epage: www.elsev ier .com/ locate /ar r
eview
re dopamine derivatives implicated in the pathogenesis ofarkinson’s disease?
arco Bisaglia ∗, Roberta Filograna, Mariano Beltramini, Luigi Bubaccoolecular Physiology and Biophysics Unit, Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35121 Padova, Italy
r t i c l e i n f o
rticle history:eceived 11 November 2013eceived in revised form6 December 2013ccepted 23 December 2013vailable online xxx
eywords:
a b s t r a c t
Parkinson’s disease (PD) is the most common motor system disorder affecting 1–2% of people over theage of sixty-five. Although PD is generally a sporadic neurological disorder, the discovery of monogenic,hereditable forms of the disease, representing 5–10% of all cases, has been very important in helping topartially delineate the molecular pathways that lead to this pathology. These mechanisms include impair-ment of the intracellular protein-degradation pathways, protein aggregation, mitochondria dysfunction,oxidative stress and neuroinflammation. Some of these features are also supported by post-mortem anal-yses. One of the main pathological hallmarks of PD is the preferential degeneration of dopaminergic
opamineopamine-quinonesitochondriaxidative stressarkinson’s disease
neurons, which supports a direct role of dopamine itself in promoting the disorder. This review presents acomprehensive overview of the existing literature that links the aforementioned pathways to the oxida-tive chemistry of dopamine, ultimately leading to the formation of free radicals and reactive quinonespecies. We emphasize, in particular, how the reaction of dopamine-derived quinones with several cellu-lar targets could foster the processes involved in the pathogenesis of PD and contribute to the progressionof the disorder.
43
44
45
© 2014 Published by Elsevier B.V.
ontents
1. Molecular pathways in PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 001.1. Clearance system impairment and protein aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 001.2. Oxidative stress and mitochondrial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 001.3. Neuroinflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Dopamine as an endogenous neurotoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. Dopamine-derived quinones and Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. Molecular pathways of DAQ toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Protein targets of DAQ. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.2. Mitochondria and DAQ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.3. DAQ and neuroinflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Which DAQ species is responsible for the toxicity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Parkinson’s disease (PD) was first discovered in 1817 by Jamesarkinson, who described this disorder as the “shaking palsy”.t is a chronic and progressive neurodegenerative disorder that
movements and postural instability. Pathologically, PD is charac-terized by a preferential degeneration of neurons in the SubstantiaNigra pars compacta (SNpc), resulting in a decrease of dopamine
Please cite this article in press as: Bisaglia, M., et al., Are dopamine derivaRes. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2013.12.009
ffects more than 6 million people worldwide (www.epda.eu.com).he main clinical feature of PD is the presence of several motorymptoms, which include resting tremor, rigidity, slowness of
∗ Corresponding author. Tel.: +39 0498276329; fax: +39 0498276300.E-mail address: [email protected] (M. Bisaglia).
568-1637/$ – see front matter © 2014 Published by Elsevier B.V.ttp://dx.doi.org/10.1016/j.arr.2013.12.009
46
47
48
levels in its striatal projections. Dopamine is pivotal for normalmovement because it allows information on movement to be trans-mitted from the SNpc to the striatum, which then initiates and
tives implicated in the pathogenesis of Parkinson’s disease? Ageing
controls the ease and balance of movement (Iversen and Iversen,2007). In addition to the loss of dopaminergic neurons, a sec-ond pathological feature of PD is the presence of cytoplasmicinclusions known as Lewy bodies (LB). Numerous molecules have
49
50
51
52
ING Model
A
2 earch
bn(e(
fPirlf2yfaai2
1
1
e�fTdeopse(ittTdfao2iot(lirmis2
1
aooga
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
ARTICLERR 489 1–8
M. Bisaglia et al. / Ageing Res
een identified within LBs (Shults, 2006), but the most promi-ent of these are ubiquitin and fibrillar aggregates of �-synucleinSpillantini et al., 1997), although the role of LB in causing the dis-ase has been the subject of considerable debate and uncertaintyRoss and Poirier, 2005).
Most forms of PD are sporadic, but in approximately 5% of cases,amiliar inheritance is observed. Although the etiopathogenesis ofD remains elusive, genetic-associated forms have provided somenteresting evidence on pathways involved in such a multifacto-ial disorder, including ubiquitin–proteasome system deregulation,eading to protein misfolding and aggregation, mitochondrial dys-unction and increased oxidative stress (Cookson, 2012; Lee and Liu,008; Shen and Cookson, 2004). Evidence from post-mortem anal-ses on PD patients also supports the impairment of mitochondrialunction, especially at the level of complex I, and oxidative damages contributing factors (Beal, 2003). In addition, previous studieslso emphasized the presence of neuroinflammation, highlightingts role in the progression of the disease (Beal, 2003; Hirsch et al.,005).
. Molecular pathways in PD
.1. Clearance system impairment and protein aggregation
The first evidence of genetic inheritance in PD was the discov-ry in 1997 of a point mutation in the SNCA gene, which encodes-synuclein (Polymeropoulos et al., 1997). �-Synuclein was also
ound to be the major component of LB (Spillantini et al., 1997).his observation, together with the discovery that �-synuclein geneuplication (Chartier-Harlin et al., 2004) and triplication (Singletont al., 2003) cause autosomal dominant PD, demonstrated the rolef protein aggregation in the pathogenesis of PD. Remarkably, theresence of LB in the brains of patients with sporadic PD alsouggests a key role for �-synuclein in the pathogenesis of the dis-ase. As �-synuclein aggregation is dependent on concentrationWood et al., 1999), a way to induce protein aggregation is throughmpairment of the cellular clearance pathways. In eukaryotic cells,he ubiquitin–proteasome and autophagy-lysosome pathways arehe two main routes of proteins clearance (Rubinsztein, 2006).he role of the ubiquitin–proteasome system in PD became evi-ent after mutations in the parkin protein were found in familiarorms of PD (Kitada et al., 1998; Leroy et al., 1998). Parkin isn E3 ubiquitin-protein ligase responsible for ubiquitin labelingf substrate proteins in preparation for their degradation by the6S proteasome. Parkin also plays a fundamental role in promot-
ng mitophagy of dysfunctional mitochondria following the lossf mitochondrial membrane potential (Narendra et al., 2009). Athe same time, malfunctioning of chaperone-mediated autophagyCMA) has also been described in PD (Cuervo et al., 2004). In particu-ar, the pathogenic A53T and A30P �-synuclein mutants describedn familial forms of PD have a high binding affinity for the CMAeceptor, but, despite their tight interaction with the lysosomalembrane, they cannot translocate into the lysosomal lumen. More
mportantly, they block the uptake and degradation of other CMAubstrates, leading to a general CMA blockage (Rumchev et al.,004).
.2. Oxidative stress and mitochondrial dysfunction
Oxidative stress occurs when the ability of the endogenousntioxidant systems is overwhelmed by the generation of reactive
Please cite this article in press as: Bisaglia, M., et al., Are dopamine derivaRes. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2013.12.009
xygen species (ROS). Nucleic acids, both RNA and DNA, undergoxidative damage, with DNA damage occurring most readily atuanine bases. Free radicals can peroxidate unsaturated fattycids, resulting in lipid degradation and cell membrane damage.
PRESSReviews xxx (2014) xxx– xxx
ROS-induced modification of proteins often leads to either a lossfunction or protein aggregation. Accordingly, an increase in 8-hydroxy-2-deoxy guanosine, 4-hydroxy-2,3-nonenal and proteincarbonylation, which are, respectively, markers of DNA damage,lipid peroxidation and protein oxidation, have all been detected inthe SNpc of PD patients (Alam et al., 1997; Floor and Wetzel, 1998;Yoritaka et al., 1996; Zhang et al., 1999).
The direct relationship between mitochondrial dysfunction andPD was proposed after the description of complex I deficiency inthe SNpc of patients who had died from PD (Schapira et al., 1989,1990). Consistent with the notion that complex I is the main mito-chondrial site of superoxide radical production (Murphy, 2009),these mitochondrial dysfunctions were observed in associationwith increased oxidative stress, emphasizing the interrelation-ship between these events (Owen et al., 1996; Schapira, 1995).Additional support for the involvement of mitochondria in PDpathogenesis emerged from the identification of genetic causes offamilial PD. Specifically, mutations in three genes, encoding parkin,DJ-1 and PINK1, are the cause of recessive forms of parkinsonism(Bonifati et al., 2003; Kitada et al., 1998; Valente et al., 2004). Inter-estingly, the major common functional effects of all three genesrelate to mitochondrial function and oxidative damage, suggest-ing a potential overlap among the pathways that lead to recessiveparkinsonism. Both parkin and PINK1 proteins are also criticallyinvolved in the regulation of mitochondrial dynamics and in theselective removal of damaged mitochondria through mitophagy.Consequentially, dysfunction of these proteins leads to impairedmitochondrial morphology and integrity (Bueler, 2010; Exner et al.,2007; Pogson et al., 2011). Although the precise biological functionof DJ-1 is not known, it has been proposed that it may play a rolein the cellular responses to oxidative stress (Cookson, 2012). Theimpairment of mitochondrial function in sporadic PD is also sup-ported by evidence that exposure to environmental toxins, knownto damage mitochondrial functions, have been identified as a sig-nificant risk factor for PD. These same toxins produce parkinsonianphenotypes when used in animal models (see (Bove and Perier,2012) for a review).
1.3. Neuroinflammation
The inflammatory response associated with cell loss in thedopaminergic nigrostriatal tract and, more generally, the role ofimmune mechanisms is increasingly recognized in PD progression(see (Hirsch and Hunot, 2009) for a review). Microglia cells arethe resident macrophages of the brain and, as such, they playcritical roles in the development and maintenance of the neu-ral environment. In the mature brain, microglia typically existin a resting state characterized by a ramified morphology thatcontinuously surveys the surrounding tissue (Nimmerjahn et al.,2005). Upon activation, following perturbations in the brain’smicroenvironment or changes in the neuronal structure, microgliadevelop a series of responses to produce mediators that help toeliminate the source of proinflammatory signals (Streit, 2002).However, under some circumstances, such as the presence of�-synuclein aggregates or of neuromelanin (NM) released fromdying neurons, microglia can become over-activated and inducesignificant detrimental neurotoxic effects by perpetuating theproinflammatory response (Kim et al., 2013; Theodore et al.,2008; Zhang et al., 2005). Post-mortem studies have reported thepresence of activated microglial cells within the SNpc of patientswith Parkinson’s disease (McGeer et al., 1988). In addition, proin-flammatory cytokines, such as IFN-�, TNF� and IL-1, coordinate the
tives implicated in the pathogenesis of Parkinson’s disease? Ageing
action of microglia and PD patients have been found with elevatedlevels of TNF� and IFN-� in the cerebrospinal fluid and braintissue (Mogi et al., 1994, 1996). Consistent with the notion that DAneurons have an increased vulnerability to oxidative insults, it has
173
174
175
176
ARTICLE IN PRESSG Model
ARR 489 1–8
M. Bisaglia et al. / Ageing Research Reviews xxx (2014) xxx– xxx 3
Proteasome dysfunction CMA impairment Neuroinflammation
III III IV V
mPTP
Mitochondrial complex I dysfunction
and mPTP opening
DNA-DAQ adducts
Protein-DAQ adducts
Neuromelanin
NH2
O
ODopamine-o-quinone (DQ)
O
O NH
Aminochrome (AC)
O
O NH
Indole-5,6-quinone (IQ)
Dopamine-derived quinones
Lysosome
F l relatt
bcfmdra
2
cefnuteoird
rw1
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
ig. 1. Molecular pathways of DAQ toxicity. The picture summarizes the potentiahrough which DAQs could promote the disorder.
een suggested that, among the factors produced by inflammatoryells, the release of superoxide by microglia might be a relevantactor fueling neurodegeneration (Qian et al., 2010). Furthermore,
icroglia can remain chronically activated in response to neuronalamage in a process that has been termed reactive microgliosis,esulting in a self-propelling and progressive cycle of microglialctivation and neuron damage (Lull and Block, 2010).
. Dopamine as an endogenous neurotoxin
None of the aforementioned molecular pathways provide aogent argument to rationalize the observed preferential degen-ration of dopaminergic neurons in PD. The proteins involved inamilial forms of the disease are not selectively expressed in thiseuronal population; conversely, most of them are abundantly andbiquitously expressed and therefore could not provide simply byheir presence a justification for dopaminergic nigrostriatal degen-ration in PD. The SNpc contains 4.5 times more microglia thanther brain regions (Kim et al., 2000), suggesting that this regions particularly exposed to inflammatory insult. Nevertheless, neu-oinflammation most likely participates to the progression of theisease rather than its etiology (Hirsch and Hunot, 2009).
Please cite this article in press as: Bisaglia, M., et al., Are dopamine derivaRes. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2013.12.009
The hypothesis that the preferential SNpc dopaminergic neu-on degeneration in PD hinges on the presence of dopamine (DA)as suggested more than 20 years ago (Hastings and Zigmond,
997). As a neurotransmitter, DA is synthesized in the cytosol
ionship between the pathological pathways involved in PD and the mechanisms
by the sequential action of tyrosine hydroxylase and aromaticamino acid decarboxylase. DA is then transferred by the vesic-ular monoamine transporter 2 inside synaptic vesicles where itis stabilized by the low pH. When the cytosolic concentration ofDA begins to exceed the physiological value, the surplus can bemetabolized via monoamine oxidase to form the highly toxic 3,4-dihydroxyphenilacetldehyde (DOPAL) (Rees et al., 2009), which inturn is converted by aldehyde dehydrogenase to the non-toxicmetabolite 3,4-dihydroxyphenylacetic acid (DOPAC). As exhaus-tively reviewed by Marchitti et al. (2007), aldehydes, includingDOPAL, form adducts with various cellular nucleophiles, result-ing in impaired cellular homeostasis, dramatically reduced enzymeactivity, and DNA damage. DOPAL accumulation and/or impaireddetoxification have been hypothesized to play a role in the patho-genesis of PD (Eisenhofer et al., 2004; Jinsmaa et al., 2011; Wey et al.,2012). Accordingly, it was recently reported that patients who diedwith PD had an elevated DOPAL-to-DOPAC ratio in caudate andputamen (Goldstein et al., 2011).
At the neutral cytosolic pH (approximately 7.0–7.4), DA isnot stable and it can self-oxidize. The presence of NM, whichis responsible for the dark pigmentation of SNpc, demonstratesthat dopamine oxidation takes place inside dopaminergic neurons.
tives implicated in the pathogenesis of Parkinson’s disease? Ageing
Accordingly, the self-oxidation of catechols to quinones with thesubsequent addition to thiol groups has been demonstrated in thebrain (Fornstedt et al., 1986). The first consequence of the redoxreactions specific to DA is an increase in oxidative stress through the
223
224
225
226
ING Model
A
4 earch
porlsdaG
3
aslDb(dptowasaSavIhcettaat
4
rmcicgstunmgmTdcHo
4
mt
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
ARTICLERR 489 1–8
M. Bisaglia et al. / Ageing Res
roduction of reactive oxygen species (ROS). In fact, self-oxidationf DA has been demonstrated to produce both superoxide anionadical and hydrogen peroxide (Klegeris et al., 1995). While lowevels of ROS can have important physiological functions in localignaling (Valko et al., 2007), an excess of ROS production can beamaging to nucleic acids, lipids and proteins, leading to an over-ll progressive decline of their function in the cell (Sanders andreenamyre, 2013).
. Dopamine-derived quinones and Parkinson’s disease
In addition to ROS production, the self-oxidation of DA canlso generate DA-derived quinones (DAQ). These electron-deficientpecies are very reactive toward nucleophiles present in the cell,eading to cellular damage specifically to dopaminergic neurons.A oxidation-derived toxicity in vivo was clearly demonstratedy injection of high concentrations of DA into the rat striatumHastings et al., 1996). After the injections, the investigatorsetected the oxidation products of DA and DOPAC as both free androtein-bound cysteinyl-DA and cysteinyl-DOPAC. This was one ofhe first pieces of evidence indicating that the oxidation productsf DA bind to proteins in the striatum, an event that was correlatedith the specific loss of dopaminergic terminals. More recently,
nalyzing four different brain regions of 2–15-month-old rats, apecific age-dependent increase of cytosolic DAQ was observednd correlated with the formation quinoprotein adducts in theNpc (Wang et al., 2011). It has been suggested that quinoproteindduct formation may play a role in the age-dependent selectiveulnerability of SNpc dopaminergic neurons (Wang et al., 2011).nterestingly, cysteinyl DA and DOPAC adducts were found to beigher in the SNpc of postmortem brain samples from PD patients inomparison to normal control subjects (Spencer et al., 1998). Nev-rtheless, this conclusion must be taken with caution because allhe patients were treated with L-DOPA to alleviate their PD symp-oms. Fig. 1 summarizes the potential relationship between theforementioned pathological pathways and the purported mech-nisms through which dopamine-derived quinones could promotehe disorder. The mechanisms will be discussed in the next sections.
. Molecular pathways of DAQ toxicity
As mentioned above, DAQs are electrophilic species that caneact with many different cellular nucleophiles. DNA-adduct for-ation has been demonstrated in peroxidase-containing HL-60
ells and in human glioblastoma cells treated with DA, suggest-ng that covalent binding of quinones to cellular DNA in vitro mayontribute to the neurotoxic effects observed in catecholaminer-ic brain regions (Levay and Bodell, 1993). More recently, anothertudy demonstrated in vitro that the reaction of DAQs with DNAo form depurinating adducts becomes fast enough to be relevantnder acidic conditions. Although their levels appeared nominal ateutral pH, a limited number of events in the absence of a rescueechanism could accumulate over time, so that the authors sug-
ested that the apurinic sites formed in the DNA could generateutations that may lead to neurodegeneration (Zahid et al., 2011).
his hypothesis is particularly attractive in the case of mitochon-rial DNA, which codes for 13 proteins located in the respiratoryhain, 7 of which are subunits of complex I (Lestienne et al., 1990).ence such modification could be responsible for the loss of activityf complex I observed in PD.
.1. Protein targets of DAQ
Please cite this article in press as: Bisaglia, M., et al., Are dopamine derivaRes. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2013.12.009
Among all the possible targets of DAQ, proteins are by far theost studied, in particular in relation to the reactivity of their cys-
eine residues. Because these residues are often located at the active
PRESSReviews xxx (2014) xxx– xxx
site of the proteins, it has been proposed that their covalent mod-ification by DAQ results in impairment of protein function withpotentially deleterious effects on the cell (LaVoie and Hastings,1999). For example, two different in vitro studies have demon-strated that DAQs covalently modify the sulfhydryl groups oftyrosine hydroxylase, the rate-limiting enzyme in catecholaminebiosynthesis, resulting in the formation of cysteinyl-catechols witha loss of enzymatic activity (Kuhn et al., 1999; Xu et al., 1998).
More recently, DAQ-binding to parkin has been reported indopaminergic MES23.5 and SH-SY5Y neuronal cells (LaVoie et al.,2005). The binding of DAQ to this protein has been demonstratedto promote parkin aggregation and to inactivate its ubiquitin ligaseactivity. Accordingly, proteasomal inhibition has been observed invitro after treatment of rabbit reticulocyte lysates with increasingamounts of quinones derived from dopamine, DOPA and DOPAC(Zafar et al., 2006). The investigators emphasized, in particular, howonly quinones rather than ROS were responsible for proteasomaldysfunction. A similar conclusion was proposed in another inde-pendent study based on the use of dopaminergic MN9D cells (Zhouand Lim, 2009).
Another study has associated DAQ modifications of �-synucleinwith the impairment of the CMA degradation pathway for othersubstrates (Martinez-Vicente et al., 2008). More precisely, it wasobserved that in isolated lysosomes, DAQ-modified �-synucleinbinds tightly to the lysosomal membrane, but it translocates poorlyinto lysosomes and blocks the lysosomal uptake of other CMA sub-strates. The authors also demonstrated that in postnatally derivedmouse ventral midbrain cultures, which encompass the SN andcontain approximately 40% dopaminergic neurons, an increasedsteady state level of DA inhibited the proportion of autophagy dueto CMA activity, but this effect was not observed in dopaminergicneuronal cultures lacking �-synuclein. The observation led to theconclusion that the cellular presence of �-synuclein is required toblock the lysosomal uptake (Martinez-Vicente et al., 2008).
In the past years, the interaction between �-synuclein and DAQhas been extensively studied. Conway et al. first reported thatincubation of the protein in the presence of DA inhibits fibril for-mation by stabilizing oligomeric species (Conway et al., 2001). Itwas then proposed that the formation of covalent �-synuclein/DAQadducts could induce the development of toxic annular protofib-rils, which are able to permeate membranes through a mechanismtypical of pore forming toxins (Volles and Lansbury, 2003). Sincethen, a number of studies have appeared in the literature aim-ing to deepen our understanding of the interaction between DAQand �-synuclein, but the results have often been contradictory, inparticular, regarding the covalent or non-covalent nature of theadducts and their secondary structures (see (Leong et al., 2009)for a review). A number of these studies suggested the forma-tion of covalent �-synuclein/DAQ adducts (Cappai et al., 2005;Conway et al., 2001; Li et al., 2004, 2005), but convincing datawere also presented for a non-covalent interaction between DAQand the 125YEMPS129 region of �-synuclein (Mazzulli et al., 2007;Norris et al., 2005). The coexistence of covalent and non-covalentoligomers currently appears to be the most likely scenario withthe covalent adducts accounting for a small fraction (5–15%) ofthe total protein (Bisaglia et al., 2010b; Conway et al., 2001; Liet al., 2004). Although researchers have been tempted to associate�-synuclein/DAQ adducts to �-sheet-rich protofibrils, works fromdifferent groups have demonstrated that after the interaction withDAQ, �-synuclein maintains an unstructured conformation, anal-ogous to that of its monomeric state (Bisaglia et al., 2010b; Rekaset al., 2010).
tives implicated in the pathogenesis of Parkinson’s disease? Ageing
In addition to parkin and �-synuclein, another protein involvedin familiar forms of PD, DJ-1, has been suggested to be modifiedby DAQ (Van Laar et al., 2009) and the structural details of theseinteractions have been recently investigated (Girotto et al., 2012).
349
350
351
352
ING Model
A
earch
DateDtta(fs(Daat
ime2gfmmtaatiwrbWagDeempc
ip(GmIni
4
aahciapmiCN
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
ARTICLERR 489 1–8
M. Bisaglia et al. / Ageing Res
J-1 seems to be implicated in PD through a loss-of-function mech-nism (da Costa, 2007; Olzmann et al., 2004). However, in view ofhe multifunctional role of DJ-1, it is quite difficult to establish theffects of the interaction with DAQ on a given protein function.J-1 has been suggested to play a role in transcriptional regula-
ion, cell signaling and apoptosis (Junn et al., 2005; Xu et al., 2005),o possess a low-intrinsic proteolytic activity (Chen et al., 2010)nd to act as a chaperone in inhibiting �-synuclein aggregationShendelman et al., 2004). The most purported and investigatedunction of DJ-1 is its neuronal protective role against oxidativetress, although how exactly this function is carried out is not clearBishop et al., 1990). Whichever is the real physiological role ofJ-1 and the molecular pathway that correlates this protein to PD,ny of the multiple cysteine-dependent functions that have beenscribed to DJ-1 would most likely be lost upon DAQ binding tohese residues (Girotto et al., 2012).
Considering the importance that oxidative stress seems to playn the pathogenesis of PD and the role of mitochondria as the
ain source of superoxide radicals in cells, we and other groupsvaluated the interplay between DAQ and superoxide dismutase
(SOD2) in the pathogenesis of PD. SOD2 is a mitochondrial man-anese enzyme, which plays a fundamental role in detoxifying cellsrom noxious free radicals by transforming superoxide radical into
olecular oxygen and hydrogen peroxide within mitochondria. Byeans of two different experimental approaches, it has been shown
hat SOD2 is a target of DAQ in rat brain mitochondria. In the firstpproach, by using a combination of fluorescent probes directedgainst cysteine or lysine residues, the investigators demonstratedhat DA oxidation results in the loss of mitochondrial proteins,ncluding SOD2 (Van Laar et al., 2008). In the second study, SOD2
as identified as one of the proteins modified by 14C-DAQs inat brain mitochondria (Van Laar et al., 2009). The interactionetween DAQ and SOD2 was analyzed more in depth in vitro.e found that exposure to DAQ induces loss of SOD2 enzymatic
ctivity, correlated to the concomitant formation of protein aggre-ates (Belluzzi et al., 2012). These results support the idea that aAQ-dependent decrease of the enzymatic activity of SOD2 wouldxacerbate oxidative stress, leading to neuronal dysfunction andventually to cell death. Another implication is that the chemicalodifications induced by DA oxidation products on very specific
rotein targets could affect their function and result in an amplifi-ation of the effects of DA itself.
In agreement, it has been recently demonstrated that the antiox-dant protein GPx4, which is primarily responsible for reducinghospholipid hydroperoxides, is sensitive to modification by DAQHauser et al., 2013). This modification would result in decreasedPx4 activity, GPx4 degradation and the formation of high-olecular-weight polymers containing GPx4 (Hauser et al., 2013).
t is possible that a selective loss of GPx4 activity in dopaminergiceurons might underlie the increases in lipid peroxides measured
n PD brain and could be a contributing factor in PD pathogenesis.
.2. Mitochondria and DAQ
Considering that mitochondrial electron transport chain (ETC)ctivity is very sensitive to inhibition by sulfhydryl modifyinggents such as mercurials (Gutman et al., 1970), several groupsave investigated the possibility that DA reactivity may be linked tohemical modification of ETC sulfhydryls through pathways involv-ng covalent adduct formation. In agreement with this hypothesisnd with a decreased mitochondrial complex I activity in PDatients (Schapira et al., 1989, 1990), works based on isolated brain
Please cite this article in press as: Bisaglia, M., et al., Are dopamine derivaRes. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2013.12.009
itochondria have demonstrated that DA is truly capable of inhib-ting brain mitochondrial respiration (Berman and Hastings, 1999;ohen et al., 1997; Cohen and Kesler, 1999; Gluck et al., 2002).evertheless, the mechanisms proposed are often contradictory.
PRESSReviews xxx (2014) xxx– xxx 5
In the presence of low DA concentrations (0.5–3 mM) for a shortperiod of incubation (15 min), the inhibition arises from mecha-nisms related to MAO-mediated DA turnover, supporting the ideathat the formation of H2O2 and hydroxyl radicals are responsiblefor the toxic effects (Gluck et al., 2002). At higher concentrationsof DA (5–20 mM for 15 min), the inhibition becomes increasinglyMAO-independent and arises from generation of ROS and throughthe formation of DAQ (Gluck and Zeevalk, 2004). Finally, even withlow concentrations (0.1–0.4 mM) but with prolonged exposure (upto 2 h), the DA-mediated inactivation of complex I and complex IVappears to predominantly involve quinone production instead ofROS (Khan et al., 2005). Moreover, in the presence of tyrosinase,which causes rapid oxidation of dopamine to quinone products, asignificant acceleration of DA-mediated inactivation of complex Iand complex IV was observed. Conversely, the presence of reducedglutathione prevents this effect due to its quinone scavengingproperties (Khan et al., 2005). Another study noted the action ofquinone on the mitochondrial permeability transition pore (mPTP).The mPTP is a calcium-dependent, proteinaceous pore that allowsthe normally impermeable inner membrane of mitochondria tobecome permeable to solutes of <1500 Da. The change in membranepermeability leads to depolarization of the transmembrane poten-tial, release of small solutes and then proteins, osmotic swelling anda loss of oxidative phosphorylation (Berman and Hastings, 1999).It has been demonstrated that DAQ production leads to a largeincrease in resting respiration, indicative of an increase in innermembrane permeability and that the oxidation of DA to DAQ resultsin an increase in mitochondrial swelling, which can be inhibited bycyclosporin A, suggestive of the opening of the mPTP (Berman andHastings, 1999). With the aim of shedding some light on the mecha-nism through which DAQ can induce the opening of the mPTP, twodifferent studies carried out on the SH-SY5Y cell line (Gimenez-Xavier et al., 2006) and on isolated mitochondria (Bisaglia et al.,2010a) demonstrated that DAQ exposure causes the oxidation ofNADH in the mitochondrial matrix, while the level of reduced GSHis not affected. These results suggest a possible mechanism of tox-icity of DAQ in mitochondria, involving the oxidation of NADH,which can lead to a variety of toxic effects. In addition to promotingthe opening of the mPTP, pyridine nucleotide oxidation could alsoaffect the activity of the ETC, particularly at the level of complexI. In fact, the electrons derived from NADH oxidation by complex Iflow through the ETC to then generate the proton gradient used bythe ATP synthase complex to produce ATP (Bisaglia et al., 2010a).
4.3. DAQ and neuroinflammation
Dopaminergic neurons are characterized by the presence of NM.It has been suggested that NM formation itself may be neuroprotec-tive because of both its scavenging activity toward toxic DAQs andcapacity to sequester redox active metal ions, such as iron, cop-per and manganese (Sulzer et al., 2000; Sulzer and Zecca, 2000;Zecca et al., 2003). Nevertheless, the dying neurons in PD havebeen observed to release NM in the cytoplasm and in the extra-cellular space. These events result in the loss of the intracellularprotective role of NM and in a worsening of neurodegeneration(Zecca et al., 2003, 2006). Extracellular NM has been suggested toinduce microglia activation leading to chronic neuroinflammation(Zecca et al., 2003, 2006). In addition to activating microglia in apolymeric form like NM, DAQs themselves have been shown to pro-mote an inflammatory response in cellular models. By analyzing theDAQ-induced alteration in the gene expression profile of microglia,the authors reported enhancement of the following responses: (i)
tives implicated in the pathogenesis of Parkinson’s disease? Ageing
expression of genes that contribute to inflammatory processes;(ii) cell and membrane damage; (iii) cytokine production; as wellas a reduction of “neuronally protective” receptors on microglia(Kuhn et al., 2006). Another group showed that DAQ-modified
477
478
479
480
ING Model
A
6 earch
cStmara
5
s5rrsttwis(qptoAirtsd(oswr
6
tWdtcdtAgtctSottor
A
o
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
ARTICLERR 489 1–8
M. Bisaglia et al. / Ageing Res
ell membranes could cause microglial activation (Le et al., 2001).pecifically, the levels of O2
−, H2O2, and NO were found to be 4-o 14-fold higher than in untreated microglia cultures. Although
icroglial activation results in the release of several cytokinesnd ROS, which can both potentially mediate a tissue-destructiveesponse, dopaminergic cell injury seems to be selectively medi-ted by nitric oxide and H2O2 (Le et al., 2001).
. Which DAQ species is responsible for the toxicity?
The oxidation of DA generates three monomeric quinonepecies, dopamine-o-quinone (DQ), aminochrome (AC) and indole-,6-quinone (IQ) (Bisaglia et al., 2007), which are all potentiallyeactive in a cellular environment. Dopamine-derived quinoneeactivity has been typically ascribed to DQ. This electron-deficientpecies reacts very quickly with the cysteinyl residues of pro-eins while the reactivity toward other nucleophilic amino acids isoo low to kinetically compete with its intramolecular cyclization,hich leads to the formation of AC (Tse et al., 1976). Accordingly,
n the case of DJ-1, it has been demonstrated by NMR and masspectrometry that DQ is able to react with both Cys53 and Cys106Girotto et al., 2012). Although in the case of parkin, the interactinguinone species have not been characterized, considering that therotein has 35 cysteinyl residues, it appears very likely that DQ ishe species that reacts in this case as well. In contrast, on the basisf indirect evidence, it has been proposed that IQ, rather than DQ orC, are the most reactive quinone species toward �-synuclein, lead-
ng to the suggestion that the IQ reactivity could represent a generaleaction pathway whenever cysteinyl residues are absent or whenhey are sterically protected (Bisaglia et al., 2007). With the aim ofhedding some light on the reactivity between DAQ and mitochon-ria, the reactivity of DQ, AC and IQ toward NADH and glutathioneGSH) has been analyzed in depth and a very diverse behavior wasbserved for the different DAQs studied (Bisaglia et al., 2010a). Con-istent with the previous hypothesis, DQ and IQ were very reactiveith both NADH and GSH, while AC did not show any appreciable
eactivity (Bisaglia et al., 2010a).
. Conclusion
The etiopathogenesis of PD is still elusive and, at present, noherapies are available to arrest the progression of the disease.
hile PD is mostly a sporadic disorder, the familiar forms of theisease have allowed the definition of the molecular pathwayshat could also be involved in the idiopathic forms. These includelearance system impairment and protein aggregation, mitochon-ria dysfunction, oxidative stress and neuroinflammation. Some ofhese processes have been corroborated by post-mortem analyses.lthough it is now clear that PD is a multifactorial disorder in whichenetic susceptibilities and environmental factors contribute tohe generation of the clinical manifestation, some common aspectsould be present in most if not all cases of PD. A distinctive feature ofhe disease is the preferential loss of dopaminergic neurons in theNpc, which supports a direct role for DA itself in the pathogenesisf PD. In this review, we have outlined how DA could contribute tohe aforementioned pathways associated with the disorder. In par-icular, the oxidative chemistry of cytosolic DA, with the formationf free radicals and reactive quinone species, could play a pivotalole in the progression of PD.
Please cite this article in press as: Bisaglia, M., et al., Are dopamine derivaRes. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2013.12.009
cknowledgments
This work was supported by grants obtained from the Universityf Padova (PRAT2010-CPDA103503; PRAT2012-124045) and the
PRESSReviews xxx (2014) xxx– xxx
Italian Ministry of Education, University and Research (PRIN2010-M2JARJ).
References
Alam, Z.I., Daniel, S.E., Lees, A.J., Marsden, D.C., Jenner, P., Halliwell, B., 1997. A gener-alised increase in protein carbonyls in the brain in Parkinson’s but not incidentalLewy body disease. J. Neurochem. 69, 1326–1329.
Beal, M.F., 2003. Mitochondria, oxidative damage, and inflammation in Parkinson’sdisease. Ann. N. Y. Acad. Sci. 991, 120–131.
Belluzzi, E., Bisaglia, M., Lazzarini, E., Tabares, L.C., Beltramini, M., Bubacco, L., 2012.Human SOD2 modification by dopamine quinones affects enzymatic activity bypromoting its aggregation: possible implications for Parkinson’s disease. PLoSOne 7, e38026.
Berman, S.B., Hastings, T.G., 1999. Dopamine oxidation alters mitochondrial respi-ration and induces permeability transition in brain mitochondria: implicationsfor Parkinson’s disease. J. Neurochem. 73, 1127–1137.
Bisaglia, M., Mammi, S., Bubacco, L., 2007. Kinetic and structural analysis of theearly oxidation products of dopamine: analysis of the interactions with alpha-synuclein. J. Biol. Chem. 282, 15597–15605.
Bisaglia, M., Soriano, M.E., Arduini, I., Mammi, S., Bubacco, L., 2010a. Molecularcharacterization of dopamine-derived quinones reactivity toward NADH andglutathione: implications for mitochondrial dysfunction in Parkinson disease.Biochim. Biophys. Acta 1802, 699–706.
Bisaglia, M., Tosatto, L., Munari, F., Tessari, I., de Laureto, P.P., Mammi, S., Bubacco, L.,2010b. Dopamine quinones interact with alpha-synuclein to form unstructuredadducts. Biochem. Biophys. Res. Commun. 394, 424–428.
Bishop, S.P., Anderson, P.G., Tucker, D.C., 1990. Morphological development of therat heart growing in oculo in the absence of hemodynamic work load. Circ. Res.66, 84–102.
Bonifati, V., Rizzu, P., van Baren, M.J., Schaap, O., Breedveld, G.J., Krieger, E., Dekker,M.C., Squitieri, F., Ibanez, P., Joosse, M., van Dongen, J.W., Vanacore, N., van Swi-eten, J.C., Brice, A., Meco, G., van Duijn, C.M., Oostra, B.A., Heutink, P., 2003.Mutations in the DJ-1 gene associated with autosomal recessive early-onsetparkinsonism. Science 299, 256–259.
Bove, J., Perier, C., 2012. Neurotoxin-based models of Parkinson’s disease. Neuro-science 211, 51–76.
Bueler, H., 2010. Mitochondrial dynamics, cell death and the pathogenesis of Parkin-son’s disease. Apoptosis 15, 1336–1353.
Cappai, R., Leck, S.L., Tew, D.J., Williamson, N.A., Smith, D.P., Galatis, D., Sharples, R.A.,Curtain, C.C., Ali, F.E., Cherny, R.A., Culvenor, J.G., Bottomley, S.P., Masters, C.L.,Barnham, K.J., Hill, A.F., 2005. Dopamine promotes alpha-synuclein aggregationinto SDS-resistant soluble oligomers via a distinct folding pathway. FASEB J. 19,1377–1379.
Chartier-Harlin, M.C., Kachergus, J., Roumier, C., Mouroux, V., Douay, X., Lincoln, S.,Levecque, C., Larvor, L., Andrieux, J., Hulihan, M., Waucquier, N., Defebvre, L.,Amouyel, P., Farrer, M., Destee, A., 2004. Alpha-synuclein locus duplication as acause of familial Parkinson’s disease. Lancet 364, 1167–1169.
Chen, J., Li, L., Chin, L.S., 2010. Parkinson disease protein DJ-1 converts from azymogen to a protease by carboxyl-terminal cleavage. Hum. Mol. Genet. 19,2395–2408.
Cohen, G., Farooqui, R., Kesler, N., 1997. Parkinson disease: a new link betweenmonoamine oxidase and mitochondrial electron flow. Proc. Natl. Acad. Sci. U.S. A. 94, 4890–4894.
Cohen, G., Kesler, N., 1999. Monoamine oxidase and mitochondrial respiration. J.Neurochem. 73, 2310–2315.
Conway, K.A., Rochet, J.C., Bieganski, R.M., Lansbury Jr., P.T., 2001. Kinetic stabiliza-tion of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct.Science 294, 1346–1349.
Cookson, M.R., 2012. Parkinsonism due to mutations in PINK1, parkin, and DJ-1 andoxidative stress and mitochondrial pathways. Cold Spring Harb. Perspect. Med.2, a009415.
Cuervo, A.M., Stefanis, L., Fredenburg, R., Lansbury, P.T., Sulzer, D., 2004. Impaireddegradation of mutant alpha-synuclein by chaperone-mediated autophagy. Sci-ence 305, 1292–1295.
da Costa, C.A., 2007. DJ-1: a newcomer in Parkinson’s disease pathology. Curr. Mol.Med. 7, 650–657.
Eisenhofer, G., Kopin, I.J., Goldstein, D.S., 2004. Catecholamine metabolism: a con-temporary view with implications for physiology and medicine. Pharmacol. Rev.56, 331–349.
Exner, N., Treske, B., Paquet, D., Holmstrom, K., Schiesling, C., Gispert, S., Carballo-Carbajal, I., Berg, D., Hoepken, H.H., Gasser, T., Kruger, R., Winklhofer, K.F., Vogel,F., Reichert, A.S., Auburger, G., Kahle, P.J., Schmid, B., Haass, C., 2007. Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescuedby parkin. J. Neurosci. 27, 12413–12418.
Floor, E., Wetzel, M.G., 1998. Increased protein oxidation in human substantianigra pars compacta in comparison with basal ganglia and prefrontal cortexmeasured with an improved dinitrophenylhydrazine assay. J. Neurochem. 70,268–275.
Fornstedt, B., Rosengren, E., Carlsson, A., 1986. Occurrence and distribution of 5-
tives implicated in the pathogenesis of Parkinson’s disease? Ageing
S-cysteinyl derivatives of dopamine, dopa and dopac in the brains of eightmammalian species. Neuropharmacology 25, 451–454.
Gimenez-Xavier, P., Gomez-Santos, C., Castano, E., Francisco, R., Boada, J., Unzeta,M., Sanz, E., Ambrosio, S., 2006. The decrease of NAD(P)H has a prominent rolein dopamine toxicity. Biochim. Biophys. Acta 1762, 564–574.
617
618
619
620
621
ING Model
A
earch
G
G
G
G
G
H
H
H
H
H
I
J
J
K
K
K
K
K
K
K
L
L
L
L
L
L
L
L
L
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
637
638
639
640
641
642
643
644
645
646
647
648
649
650
651
652
653
654
655
656
657
658
659
660
661
662
663
664
665
666
667
668
669
670
671
672
673
674
675
676
677
678
679
680
681
682
683
684
685
686
687
688
689
690
691
692
693
694
695
696
697
698
699
700
701
702
703
704
705
706
707
708
709
710
711
712
713
714
715
716
717
718
719
720
721
722
723
724
725
726
727
728
729
730
731
732
733
734
735
736
737
738
739
740
741
742
743
744
745
746
747
748
749
750
751
752
753
754
755
756
757
758
759
760
761
762
763
764
765
766
767
768
769
770
771
772
773
774
775
776
777
778
779
780
781
782
783
784
785
786
787
788
ARTICLERR 489 1–8
M. Bisaglia et al. / Ageing Res
irotto, S., Sturlese, M., Bellanda, M., Tessari, I., Cappellini, R., Bisaglia, M., Bubacco, L.,Mammi, S., 2012. Dopamine-derived quinones affect the structure of the redoxsensor DJ-1 through modifications at Cys-106 and Cys-53. J. Biol. Chem. 287,18738–18749.
luck, M., Ehrhart, J., Jayatilleke, E., Zeevalk, G.D., 2002. Inhibition of brain mitochon-drial respiration by dopamine: involvement of H(2)O(2) and hydroxyl radicalsbut not glutathione-protein-mixed disulfides. J. Neurochem. 82, 66–74.
luck, M.R., Zeevalk, G.D., 2004. Inhibition of brain mitochondrial respirationby dopamine and its metabolites: implications for Parkinson’s disease andcatecholamine-associated diseases. J. Neurochem. 91, 788–795.
oldstein, D.S., Sullivan, P., Holmes, C., Kopin, I.J., Basile, M.J., Mash, D.C., 2011. Cat-echols in post-mortem brain of patients with Parkinson disease. Eur. J. Neurol.18, 703–710.
utman, M., Mersmann, H., Luthy, J., Singer, T.P., 1970. Action of sulfhydryl inhibitorson different forms of the respiratory chain-linked reduced nicotinamide-adenine dinucleotide dehydrogenase. Biochemistry 9, 2678–2687.
astings, T.G., Lewis, D.A., Zigmond, M.J., 1996. Role of oxidation in the neurotoxiceffects of intrastriatal dopamine injections. Proc. Natl. Acad. Sci. U. S. A. 93,1956–1961.
astings, T.G., Zigmond, M.J., 1997. Loss of dopaminergic neurons in parkinsonism:possible role of reactive dopamine metabolites. J. Neural. Transm. Suppl. 49,103–110.
auser, D.N., Dukes, A.A., Mortimer, A.D., Hastings, T.G., 2013. Dopamine quinonemodifies and decreases the abundance of the mitochondrial selenoprotein glu-tathione peroxidase 4. Free Radic. Biol. Med. 65C, 419–427.
irsch, E.C., Hunot, S., 2009. Neuroinflammation in Parkinson’s disease: a target forneuroprotection? Lancet Neurol. 8, 382–397.
irsch, E.C., Hunot, S., Hartmann, A., 2005. Neuroinflammatory processes in Parkin-son’s disease. Parkinsonism Relat. Disord. 11 (Suppl 1), S9L S15.
versen, S.D., Iversen, L.L., 2007. Dopamine: 50 years in perspective. Trends Neurosci.30, 188–193.
insmaa, Y., Florang, V.R., Rees, J.N., Mexas, L.M., Eckert, L.L., Allen, E.M., Anderson,D.G., Doorn, J.A., 2011. Dopamine-derived biological reactive intermediates andprotein modifications: implications for Parkinson’s disease. Chem. Biol. Interact.192, 118–121.
unn, E., Taniguchi, H., Jeong, B.S., Zhao, X., Ichijo, H., Mouradian, M.M., 2005. Inter-action of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activityand cell death. Proc. Natl. Acad. Sci. U. S. A. 102, 9691–9696.
han, F.H., Sen, T., Maiti, A.K., Jana, S., Chatterjee, U., Chakrabarti, S., 2005. Inhibitionof rat brain mitochondrial electron transport chain activity by dopamine oxida-tion products during extended in vitro incubation: implications for Parkinson’sdisease. Biochim. Biophys. Acta 1741, 65–74.
im, C., Ho, D.H., Suk, J.E., You, S., Michael, S., Kang, J., Joong Lee, S., Masliah, E., Hwang,D., Lee, H.J., Lee, S.J., 2013. Neuron-released oligomeric alpha-synuclein is anendogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun.4, 1562.
im, W.G., Mohney, R.P., Wilson, B., Jeohn, G.H., Liu, B., Hong, J.S., 2000. Regionaldifference in susceptibility to lipopolysaccharide-induced neurotoxicity in therat brain: role of microglia. J. Neurosci. 20, 6309–6316.
itada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S.,Yokochi, M., Mizuno, Y., Shimizu, N., 1998. Mutations in the parkin gene causeautosomal recessive juvenile parkinsonism. Nature 392, 605–608.
legeris, A., Korkina, L.G., Greenfield, S.A., 1995. Autoxidation of dopamine: a com-parison of luminescent and spectrophotometric detection in basic solutions.Free Radic. Biol. Med. 18, 215–222.
uhn, D.M., Arthur Jr., R.E., Thomas, D.M., Elferink, L.A., 1999. Tyrosine hydroxylaseis inactivated by catechol-quinones and converted to a redox-cycling quinopro-tein: possible relevance to Parkinson’s disease. J. Neurochem. 73, 1309–1317.
uhn, D.M., Francescutti-Verbeem, D.M., Thomas, D.M., 2006. Dopamine quinonesactivate microglia and induce a neurotoxic gene expression profile: relationshipto methamphetamine-induced nerve ending damage. Ann. N. Y. Acad. Sci. 1074,31–41.
aVoie, M.J., Hastings, T.G., 1999. Dopamine quinone formation and protein modifi-cation associated with the striatal neurotoxicity of methamphetamine: evidenceagainst a role for extracellular dopamine. J. Neurosci. 19, 1484–1491.
aVoie, M.J., Ostaszewski, B.L., Weihofen, A., Schlossmacher, M.G., Selkoe, D.J., 2005.Dopamine covalently modifies and functionally inactivates parkin. Nat. Med. 11,1214–1221.
e, W., Rowe, D., Xie, W., Ortiz, I., He, Y., Appel, S.H., 2001. Microglial activation anddopaminergic cell injury: an in vitro model relevant to Parkinson’s disease. J.Neurosci. 21, 8447–8455.
ee, F.J., Liu, F., 2008. Genetic factors involved in the pathogenesis of Parkinson’sdisease. Brain Res. Rev. 58, 354–364.
eong, S.L., Cappai, R., Barnham, K.J., Pham, C.L., 2009. Modulation of alpha-synucleinaggregation by dopamine: a review. Neurochem. Res. 34, 1838–1846.
eroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., Harta, G., Brownstein,M.J., Jonnalagada, S., Chernova, T., Dehejia, A., Lavedan, C., Gasser, T., Stein-bach, P.J., Wilkinson, K.D., Polymeropoulos, M.H., 1998. The ubiquitin pathwayin Parkinson’s disease. Nature 395, 451–452.
estienne, P., Nelson, J., Riederer, P., Jellinger, K., Reichmann, H., 1990. Normal mito-chondrial genome in brain from patients with Parkinson’s disease and complex
Please cite this article in press as: Bisaglia, M., et al., Are dopamine derivaRes. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2013.12.009
I defect. J. Neurochem. 55, 1810–1812.evay, G., Bodell, W.J., 1993. Detection of dopamine–DNA adducts: potential role in
Parkinson’s disease. Carcinogenesis 14, 1241–1245.i, H.T., Lin, D.H., Luo, X.Y., Zhang, F., Ji, L.N., Du, H.N., Song, G.Q., Hu, J., Zhou, J.W., Hu,
H.Y., 2005. Inhibition of alpha-synuclein fibrillization by dopamine analogs via
PRESSReviews xxx (2014) xxx– xxx 7
reaction with the amino groups of alpha-synuclein, Implication for dopaminer-gic neurodegeneration. FEBS J. 272, 3661–3672.
Li, J., Zhu, M., Manning-Bog, A.B., Di Monte, D.A., Fink, A.L., 2004. Dopamine and L-dopa disaggregate amyloid fibrils: implications for Parkinson’s and Alzheimer’sdisease. FASEB J. 18, 962–964.
Lull, M.E., Block, M.L., 2010. Microglial activation and chronic neurodegeneration.Neurotherapeutics 7, 354–365.
Marchitti, S.A., Deitrich, R.A., Vasiliou, V., 2007. Neurotoxicity and metabolismof the catecholamine-derived 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase. Pharma-col. Rev. 59, 125–150.
Martinez-Vicente, M., Talloczy, Z., Kaushik, S., Massey, A.C., Mazzulli, J., Mosharov,E.V., Hodara, R., Fredenburg, R., Wu, D.C., Follenzi, A., Dauer, W., Przedborski,S., Ischiropoulos, H., Lansbury, P.T., Sulzer, D., Cuervo, A.M., 2008. Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J. Clin. Invest.118, 777–788.
Mazzulli, J.R., Armakola, M., Dumoulin, M., Parastatidis, I., Ischiropoulos, H., 2007.Cellular oligomerization of alpha-synuclein is determined by the interac-tion of oxidized catechols with a C-terminal sequence. J. Biol. Chem. 282,31621–31630.
McGeer, P.L., Itagaki, S., Boyes, B.E., McGeer, E.G., 1988. Reactive microglia are pos-itive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s diseasebrains. Neurology 38, 1285–1291.
Mogi, M., Harada, M., Narabayashi, H., Inagaki, H., Minami, M., Nagatsu, T., 1996.Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha lev-els are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism andParkinson’s disease. Neurosci. Lett. 211, 13–16.
Mogi, M., Harada, M., Riederer, P., Narabayashi, H., Fujita, K., Nagatsu, T., 1994.Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in thecerebrospinal fluid from parkinsonian patients. Neurosci. Lett. 165, 208–210.
Murphy, M.P., 2009. How mitochondria produce reactive oxygen species. Biochem.J. 417, 1–13.
Narendra, D., Tanaka, A., Suen, D.F., Youle, R.J., 2009. Parkin-induced mitophagy inthe pathogenesis of Parkinson disease. Autophagy 5, 706–708.
Nimmerjahn, A., Kirchhoff, F., Helmchen, F., 2005. Resting microglial cells are highlydynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318.
Norris, E.H., Giasson, B.I., Hodara, R., Xu, S., Trojanowski, J.Q., Ischiropoulos,H., Lee, V.M., 2005. Reversible inhibition of alpha-synuclein fibrillization bydopaminochrome-mediated conformational alterations. J. Biol. Chem. 280,21212–21219.
Olzmann, J.A., Brown, K., Wilkinson, K.D., Rees, H.D., Huai, Q., Ke, H., Levey, A.I., Li, L.,Chin, L.S., 2004. Familial Parkinson’s disease-associated L166P mutation disruptsDJ-1 protein folding and function. J. Biol. Chem. 279, 8506–8515.
Owen, A.D., Schapira, A.H., Jenner, P., Marsden, C.D., 1996. Oxidative stress andParkinson’s disease. Ann. N. Y. Acad. Sci. 786, 217–223.
Pogson, J.H., Ivatt, R.M., Whitworth, A.J., 2011. Molecular mechanisms of PINK1-related neurodegeneration. Curr. Neurol. Neurosci. Rep. 11, 283–290.
Polymeropoulos, M.H., Lavedan, C., Leroy, E., Ide, S.E., Dehejia, A., Dutra, A., Pike, B.,Root, H., Rubenstein, J., Boyer, R., Stenroos, E.S., Chandrasekharappa, S., Athanas-siadou, A., Papapetropoulos, T., Johnson, W.G., Lazzarini, A.M., Duvoisin, R.C., DiIorio, G., Golbe, L.I., Nussbaum, R.L., 1997. Mutation in the alpha-synuclein geneidentified in families with Parkinson’s disease. Science 276, 2045–2047.
Qian, L., Flood, P.M., Hong, J.S., 2010. Neuroinflammation is a key player in Parkin-son’s disease and a prime target for therapy. J. Neural Transm. 117, 971–979.
Rees, J.N., Florang, V.R., Eckert, L.L., Doorn, J.A., 2009. Protein reactivity of 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite, is dependent onboth the aldehyde and the catechol. Chem. Res. Toxicol. 22, 1256–1263.
Rekas, A., Knott, R.B., Sokolova, A., Barnham, K.J., Perez, K.A., Masters, C.L., Drew, S.C.,Cappai, R., Curtain, C.C., Pham, C.L., 2010. The structure of dopamine inducedalpha-synuclein oligomers. Eur. Biophys. J. 39, 1407–1419.
Ross, C.A., Poirier, M.A., 2005. Opinion: what is the role of protein aggregation inneurodegeneration? Nat. Rev. Mol. Cell Biol. 6, 891–898.
Rubinsztein, D.C., 2006. The roles of intracellular protein-degradation pathways inneurodegeneration. Nature 443, 780–786.
Rumchev, K., Spickett, J., Bulsara, M., Phillips, M., Stick, S., 2004. Association ofdomestic exposure to volatile organic compounds with asthma in young chil-dren. Thorax 59, 746–751.
Sanders, L.H., Greenamyre, J.T., 2013. Oxidative damage to macromolecules inhuman Parkinson disease and the rotenone model. Free Radic. Biol. Med. 62,111–120.
Schapira, A.H., 1995. Oxidative stress in Parkinson’s disease. Neuropathol. Appl.Neurobiol. 21, 3–9.
Schapira, A.H., Cooper, J.M., Dexter, D., Clark, J.B., Jenner, P., Marsden, C.D., 1990.Mitochondrial complex I deficiency in Parkinson’s disease. J. Neurochem. 54,823–827.
Schapira, A.H., Cooper, J.M., Dexter, D., Jenner, P., Clark, J.B., Marsden, C.D., 1989.Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1, 1269.
Shen, J., Cookson, M.R., 2004. Mitochondria and dopamine: new insights into reces-sive parkinsonism. Neuron 43, 301–304.
Shendelman, S., Jonason, A., Martinat, C., Leete, T., Abeliovich, A., 2004. DJ-1 is aredox-dependent molecular chaperone that inhibits alpha-synuclein aggregate
tives implicated in the pathogenesis of Parkinson’s disease? Ageing
formation. PLoS Biol. 2, e362.Shults, C.W., 2006. Lewy bodies. Proc. Natl. Acad. Sci. U. S. A. 103, 1661–1668.Singleton, A.B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan,
M., Peuralinna, T., Dutra, A., Nussbaum, R., Lincoln, S., Crawley, A., Hanson, M.,Maraganore, D., Adler, C., Cookson, M.R., Muenter, M., Baptista, M., Miller, D.,
789
790
791
792
793
ING Model
A
8 earch
S
S
S
S
S
T
T
V
V
V
V
V
W
Y., Hong, J.S., Zhang, J., 2005. Aggregated alpha-synuclein activates microglia:
794
795
796
797
798
799
800
801
802
803
804
805
806
807
808
809
810
811
812
813
814
815
816
817
818
819
820
821
822
823
824
825
826
827
828
829
830
831
832
833
834
835
836
837
838
839
840
841
842
843
844
845
846
847
848
849
850
851
852
853
854
855
856
857
858
859
860
861
862
863
864
865
866
867
ARTICLERR 489 1–8
M. Bisaglia et al. / Ageing Res
Blancato, J., Hardy, J., Gwinn-Hardy, K., 2003. alpha-Synuclein locus triplicationcauses Parkinson’s disease. Science 302, 841.
pencer, J.P., Jenner, P., Daniel, S.E., Lees, A.J., Marsden, D.C., Halliwell, B., 1998. Con-jugates of catecholamines with cysteine and GSH in Parkinson’s disease: possiblemechanisms of formation involving reactive oxygen species. J. Neurochem. 71,2112–2122.
pillantini, M.G., Schmidt, M.L., Lee, V.M., Trojanowski, J.Q., Jakes, R., Goedert, M.,1997. Alpha-synuclein in Lewy bodies. Nature 388, 839–840.
treit, W.J., 2002. Microglia as neuroprotective, immunocompetent cells of the CNS.Glia 40, 133–139.
ulzer, D., Bogulavsky, J., Larsen, K.E., Behr, G., Karatekin, E., Kleinman, M.H., Turro,N., Krantz, D., Edwards, R.H., Greene, L.A., Zecca, L., 2000. Neuromelanin biosyn-thesis is driven by excess cytosolic catecholamines not accumulated by synapticvesicles. Proc. Natl. Acad. Sci. U. S. A. 97, 11869–11874.
ulzer, D., Zecca, L., 2000. Intraneuronal dopamine-quinone synthesis: a review.Neurotox. Res. 1, 181–195.
heodore, S., Cao, S., McLean, P.J., Standaert, D.G., 2008. Targeted overexpression ofhuman alpha-synuclein triggers microglial activation and an adaptive immuneresponse in a mouse model of Parkinson disease. J. Neuropathol. Exp. Neurol.67, 1149–1158.
se, D.C., McCreery, R.L., Adams, R.N., 1976. Potential oxidative pathways of braincatecholamines. J. Med. Chem. 19, 37–40.
alente, E.M., Salvi, S., Ialongo, T., Marongiu, R., Elia, A.E., Caputo, V., Romito, L.,Albanese, A., Dallapiccola, B., Bentivoglio, A.R., 2004. PINK1 mutations are asso-ciated with sporadic early-onset parkinsonism. Ann. Neurol. 56, 336–341.
alko, M., Leibfritz, D., Moncol, J., Cronin, M.T., Mazur, M., Telser, J., 2007. Free radi-cals and antioxidants in normal physiological functions and human disease. Int.J. Biochem. Cell Biol. 39, 44–84.
an Laar, V.S., Dukes, A.A., Cascio, M., Hastings, T.G., 2008. Proteomic analysis of ratbrain mitochondria following exposure to dopamine quinone: implications forParkinson disease. Neurobiol. Dis. 29, 477–489.
an Laar, V.S., Mishizen, A.J., Cascio, M., Hastings, T.G., 2009. Proteomic identificationof dopamine-conjugated proteins from isolated rat brain mitochondria and SH-SY5Y cells. Neurobiol. Dis. 34, 487–500.
olles, M.J., Lansbury Jr., P.T., 2003. Zeroing in on the pathogenic form of
Please cite this article in press as: Bisaglia, M., et al., Are dopamine derivaRes. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2013.12.009
alpha-synuclein and its mechanism of neurotoxicity in Parkinson’s disease. Bio-chemistry 42, 7871–7878.
ang, N., Wang, Y., Yu, G., Yuan, C., Ma, J., 2011. Quinoprotein adducts accumulate inthe substantia nigra of aged rats and correlate with dopamine-induced toxicityin SH-SY5Y cells. Neurochem. Res. 36, 2169–2175.
PRESSReviews xxx (2014) xxx– xxx
Wey, M.C., Fernandez, E., Martinez, P.A., Sullivan, P., Goldstein, D.S., Strong, R., 2012.Neurodegeneration and motor dysfunction in mice lacking cytosolic and mito-chondrial aldehyde dehydrogenases: implications for Parkinson’s disease. PLoSOne 7, e31522.
Wood, S.J., Wypych, J., Steavenson, S., Louis, J.C., Citron, M., Biere, A.L., 1999.alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for thepathogenesis of Parkinson’s disease. J. Biol. Chem. 274, 19509–19512.
Xu, J., Zhong, N., Wang, H., Elias, J.E., Kim, C.Y., Woldman, I., Pifl, C., Gygi, S.P., Geula,C., Yankner, B.A., 2005. The Parkinson’s disease-associated DJ-1 protein is atranscriptional co-activator that protects against neuronal apoptosis. Hum. Mol.Genet. 14, 1231–1241.
Xu, Y., Stokes, A.H., Roskoski Jr., R., Vrana, K.E., 1998. Dopamine, in the presence oftyrosinase, covalently modifies and inactivates tyrosine hydroxylase. J. Neurosci.Res. 54, 691–697.
Yoritaka, A., Hattori, N., Uchida, K., Tanaka, M., Stadtman, E.R., Mizuno, Y.,1996. Immunohistochemical detection of 4-hydroxynonenal protein adducts inParkinson disease. Proc. Natl. Acad. Sci. U. S. A. 93, 2696–2701.
Zafar, K.S., Siegel, D., Ross, D., 2006. A potential role for cyclized quinones derivedfrom dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid in proteasomal inhi-bition. Mol. Pharmacol. 70, 1079–1086.
Zahid, M., Saeed, M., Yang, L., Beseler, C., Rogan, E., Cavalieri, E.L., 2011. Formationof dopamine quinone-DNA adducts and their potential role in the etiology ofParkinson’s disease. IUBMB Life 63, 1087–1093.
Zecca, L., Zucca, F.A., Albertini, A., Rizzio, E., Fariello, R.G., 2006. A proposed dualrole of neuromelanin in the pathogenesis of Parkinson’s disease. Neurology 67,S8–S11.
Zecca, L., Zucca, F.A., Wilms, H., Sulzer, D., 2003. Neuromelanin of the substantianigra: a neuronal black hole with protective and toxic characteristics. TrendsNeurosci. 26, 578–580.
Zhang, J., Perry, G., Smith, M.A., Robertson, D., Olson, S.J., Graham, D.G., Mon-tine, T.J., 1999. Parkinson’s disease is associated with oxidative damage tocytoplasmic DNA and RNA in substantia nigra neurons. Am. J. Pathol. 154,1423–1429.
Zhang, W., Wang, T., Pei, Z., Miller, D.S., Wu, X., Block, M.L., Wilson, B., Zhou,
tives implicated in the pathogenesis of Parkinson’s disease? Ageing
a process leading to disease progression in Parkinson’s disease. FASEB J. 19,533–542.
Zhou, Z.D., Lim, T.M., 2009. Dopamine (DA) induced irreversible proteasome inhibi-tion via DA derived quinones. Free Radic. Res. 43, 417–430.
868
869
870
871
