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Inflammation and Parkinson’s Disease Pathogenesis
Serge Przedborski, MD, PhD*
Department of Neurology, Pathology and Cell Biology, Columbia University, New York, New York, USA
Abstract: Inflammation is a neuropathological feature ofparkinsonian brains and also in experimental models of thedisease. It is believed that activated glial cells, which com-pose the majority of this inflammatory response contributeto the neurodegenerative process through the productionof toxic molecules. Therapeutic strategies geared toward
reducing inflammation and inhibiting the production ofthese glial-derived toxic molecules may be a promisingneuroprotective strategy for the treatment of Parkinson’sdisease and related conditions. � 2010 Movement DisorderSocietyKey words: Parkinson’s disease; MPTP; inflammation
Parkinson’s disease (PD) is the second most com-
mon degenerative disorder of the aging brain after Alz-
heimer’s disease.1 PD presents itself essentially as a
sporadic condition of unknown cause and for which
there is, thus far, no cure.1 Its cardinal features include
resting tremor, rigidity, akinesia, and postural instabil-
ity, forming a clinical picture readily identifiable.2 It is
now well-recognized that PD neurodegeneration is
multisystemic, involving many different neuronal path-
ways.3 Yet, the degeneration of the nigrostriatal path-
way and the ensuing deficit in brain dopamine remain,
for most clinicians and scientists, the prototypic altera-
tions of this disabling disease.1
Another well-known neuropathological feature of
PD is the presence of intraneuronal proteinaceous
inclusions, called Lewy bodies.4 Within the few spared
dopaminergic cells encountered in ventral midbrains of
PD patients, Lewy bodies are often large, can be multi-
ple, and generally occupy most of the cytoplasm.
Lewy bodies can be easily identified, either by classi-
cal histological dyes, such as hematoxylin and eosin,
or by immunohistochemistry, using antibodies raised
against alpha-synuclein or ubiquitin.4 While their path-
ogenic role remains controversial, Lewy bodies con-
tinue to be regarded as a neuropathological finding of
diagnostic value.
A third, and perhaps less well-recognized, neuro-
pathological feature of PD is the presence of a glial
response in all areas of the brain where signs of neuro-
degeneration can be found. It is on this last and partic-
ular aspect of PD neuropathology that this chapter is
centered. As discussed in-depth elsewhere,5 over the
past decades, the presence of a glial response in PD
brain tissues has drawn a major interest among
researchers, in part because of the idea that neuroin-
flammation, caused by activated glial cells, might play
an important role in the neurodegenerative process.
INFLAMMATION AND PD
It is important to stress the fact that the aforemen-
tioned glial response is a generic cellular response to
the degeneration of neighboring cells such as neurons
which is not exclusive to PD.5 Indeed, an identical
glial response can be observed in virtually all parkinso-
nian syndromes, including cases of familial PD linked
to alpha-synuclein or LRRK2 mutations6,7; cases of
multisystem atrophy or progressive supranuclear
palsy8,9; and toxic parkinsonisms related to compounds
like MPTP.10 Histological analyses have revealed that
Potential conflict of interest: None reported.
*Correspondence to: Dr. Serge Przedborski, BB-302, ColumbiaUniversity Medical Center, 650 West 168th Street, New York,New York 10032. E-mail: [email protected]
Received 22 March 2008; Accepted 27 March 2009Published online in Wiley InterScience (www.interscience.wiley.
com). DOI: 10.1002/mds.22638
S55
Movement DisordersVol. 25, Suppl. 1, 2010, pp. S55–S57� 2010 Movement Disorder Society
the composition of the glial reaction in PD and related
conditions is made of primarily astrocytes and micro-
glia and, to a much lesser extent, of T-cells. Con-
versely, there is no evidence of brain infiltration by B-
cells or polynuclear white cells in PD; the latter likely
reflects the lack of blood brain barrier damage. Based
on animal models of PD such as MPTP, 6-hydroxydo-
pamine (6-OHDA), or rotenone, it appears that the
glial response is triggered by the loss of neighboring
neurons and thus is most profound in the areas of overt
degeneration.
ROLE OF THE GLIAL REACTION IN PD
Several reviews of the subject of neuroinflammation
have clearly demonstrated that the glial reaction in
pathological situations of the CNS can play either a
beneficial or detrimental role.5,11–13 The former proper-
ties are thought to be possibly mediated by the produc-
tion of a variety of trophic factors, the uptake of any
excess of glutamate, or the removal of cell debris; the
latter can result from the production of a host of cyto-
toxic molecules ranging from reactive oxygen and
nitrogen species (ROS; RNS) to cytokines. In the case
of PD, epidemiological studies have shown that the use
of nonsteroidal anti-inflammatory drugs decreased the
risk of developing PD.14 Although risk factors cannot
be equated to pathogenic factors, these studies still pro-
vide a major impetus to the notion that inflammation
in PD can enhance the neurodegenerative process, pro-
moting both the progression and propagation of the
disease. According to this idea, it may be proposed
that, in a disease like PD, where not all neurons die at
the same time, the very first cells to succumb to the
pathological process activate the neighboring glial
cells. Once activated, glial cells, and especially micro-
glia, can engage in the production of toxic mole-
cules15,16 that can promote the demise of surrounding
compromised neurons.
INFLAMMATORY ENZYMES AND
DOPAMINERGIC NEURODEGENERATION
As indicated earlier, activated glia can produce a
host of toxic molecules including RNS and ROS. In
the context of inflammation, the main generators of
RNS and ROS are, respectively, the enzymes inducible
NOS (iNOS) and NADPH-oxidase. In the normal
CNS, iNOS is not expressed and NADPH-oxidase is
quiescent, but in patients with PD and in MPTP mice,
both iNOS and NADPH-oxidase are clearly expressed
and/or activated in glial cells in the ventral mid-
brain.17–19 These two inflammatory enzymes could
have a pathogenic role in PD, given the fact that their
lack in mutant mice is associated with a lesser loss of
dopaminergic neurons after MPTP administration.17,18
It should be noted, however, that not all inflammatory
enzymes identified in PD brain are potentially neuro-
toxic. For instance, myeloperoxidase (MPO) is an
enzyme known to be involved in dramatic inflamma-
tory events in the periphery. This enzyme was recently
identified in the CNS of PD patients and of MPTP
mice.20 Yet, the absence of MPO in mutant mice only
provided marginal attenuation against MPTP-induced
dopaminergic neurotoxicity.20
THE SINGULAR SITUATION OF
CYLCOOXYGENASE-2
Several investigators, including ourselves, have pre-
viously shown that cylcooxygenase-2 (COX-2) mRNA
and protein are highly expressed in tissues of both PD
patients and MPTP mice.21 To our surprise, this inflam-
matory enzyme was not detected in glial cells but rather
in dopaminergic neurons of PD and MPTP mouse tis-
sues.21 While this unexpected finding could suggest that
COX-2 reacted merely as a stress factor without any
pathogenic role, it is important to mention that nullify-
ing COX-2 activity, either by pharmacological agents
or genetic engineering, caused a clear attenuation of
MPTP-induced dopaminergic neurodegeneration.21 We
also found that the inflammatory response associated
with dopaminergic neurodegeneration in COX-2 knock-
out mice did not differ from that which has been
observed in their wild-type counterparts.21 This result
suggests that the beneficial role of COX-2 in the mouse
model of PD is not mediated by an inflammatory event,
but by an alterative mechanism that our ongoing studies
are attempting to identify. The take-home message here
is that not all inflammatory enzymes identified in PD
brain may be contributing to neurodegeneration neces-
sarily via an inflammatory mechanism.
DUAL PHENOTYPE OF GLIAL CELLS
T-cell alterations in PD blood22 and infiltration in
brain parenchyma of MPTP-treated mice23,24 have
been reported. Through their effector functions, T-cells
can interact with other resident cells, such as neurons
and glial cells. It has been demonstrated that upon vac-
cination against brain-derived proteins, T-cells can
gain access to the brain, where they can modulate the
S56 S. PRZEDBORSKI
Movement Disorders, Vol. 25, Suppl. 1, 2010
phenotype of the resident glial cells. More importantly,
it was shown that in several pathological settings
affecting the brain, vaccination against copolymer-1,
which is thought to behave as an analogue of myelin
basic protein, can coax glial cells to shift from a nox-
ious to a beneficial phenotype. Using such an
approach, we have tested the effect of vaccination
using copolymer-1 against MPTP toxicity.25 Here,
MPTP mice received a suspension of splenocytes puri-
fied from mice previously vaccinated with copolymer-
1.25 After this infusion of copolymer-1 splenocytes,
there was a striking attenuation of MPTP-induced tox-
icity on dopaminergic neurons.25 In these mice, there
was coincidentally a marked attenuation of the micro-
glial reaction and a significant increase in the trophic
factor contents in the ventral midbrain.25 While we
have not formally tested this possibility, it is tantaliz-
ing to suggest that copolymer-1 T-cells, once in the
brain, inhibited the microglial activation and stimulated
the production of trophic factor by astrocytes.
CONCLUSION
A glial reaction is a consistent feature of neurode-
generation in all parkinsonian syndromes. Thanks to
the use of toxic models of PD, mounting evidence
indicates that neuroinflammation may contribute to the
neurodegenerative process of PD. Because neuroin-
flammation is a multifactorial phenomenon, should its
pathogenic role be confirmed, optimal therapeutic strat-
egy will thus have to call upon the use of a cocktail of
agents to abate several of the key inflammatory media-
tors. Finally, while vaccination is still in its infancy,
preclinical results support its potential value in the
treatment of complex disease such as PD and warrant
further investigations
Acknowledgments: This work was supported by NIH/NINDS Grants RO1 AG21617 and P01 NS11766-27A1, Mor-ris K. Udall Parkinson’s Disease Research Grant P50NS38370, the US Department of Defense Grant DAMD 17-03-1, MDA/Wings Over Wall Street, and the Parkinsons Dis-ease Foundation, USA. We thank Michael Shelley for his as-sistance in preparing this manuscript.
REFERENCES
1. Dauer W, Przedborski S. Parkinson’s disease: mechanisms andmodels. Neuron 2003;39:889–909.
2. Fahn S, Przedborski S. Parkinsonism. In: Rowland LP, editor.Merritt’s Neurology, 11th ed. New York: Lippincott; 2005.p 828–846.
3. Braak H, Braak E, Yilmazer D, et al. Nigral and extranigral pa-thology in Parkinson’s disease. J Neural Transm Suppl 1995;46:15–31.
4. Shults CW. Lewy bodies. Proc Natl Acad Sci USA 2006;103:1661–1668.
5. Przedborski S. Neuroinflammation and Parkinson’s disease. In:Koller WC, Melamed E, editors. Parkinson’s disease and relateddisorders. New York: Elsevier; 2007. p 535–551.
6. Spira PJ, Sharpe DM, Halliday G, et al. Clinical and pathologicalfeatures of a Parkinsonian syndrome in a family with an Ala53Thralpha-synuclein mutation. Ann Neurol 2001;49:313–319.
7. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2cause autosomal-dominant parkinsonism with pleomorphic pa-thology. Neuron 2004;44:601–607.
8. Steele JC, Richardson JC, Olszewski J. Progressive supranuclearpalsy. Arch Neurol 1964;10:333–358.
9. Adams RD, Salam-Adams M. Striatonigral degeneration. In:Vinken PJ, Bruyn GW, Klawans HL, editors. Handbook of clini-cal neurology. Extrapyramidal disorders, Vol. 49. New York:Elsevier; 1986. p 205–212.
10. Langston JW, Forno LS, Tetrud J, et al. Evidence of active nervecell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol1999;46:598–605.
11. Wyss-Coray T, Mucke L. Inflammation in neurodegenerative dis-ease-a double-edged sword. Neuron 2002;35:419–432.
12. McGeer PL, McGeer EG. Glial cell reactions in neurodegenera-tive diseases: pathophysiology and therapeutic interventions. Alz-heimer Dis Assoc Disord 1998;12 (Suppl 2):S1–S6.
13. McGeer PL, McGeer EG. Inflammation and neurodegeneration inParkinson’s disease. Parkinsonism Relat Disord 2004;10 (Suppl1):S3–S7.
14. Chen H, Zhang SM, Hernan MA, et al. Nonsteroidal anti-inflam-matory drugs and the risk of Parkinson disease. Arch Neurol2003;60:1059–1064.
15. Kreutzberg GW. Microglia: a sensor for pathological events inthe CNS. Trends Neurosci 1996;19:312–318.
16. Streit WJ, Walter SA, Pennell NA. Reactive microgliosis. ProgNeurobiol 1999;57:563–581.
17. Liberatore G, Jackson-Lewis V, Vukosavic S, et al. Inducible ni-tric oxide synthase stimulates dopaminergic neurodegeneration inthe MPTP model of Parkinson disease. Nat Med 1999;5:1403–1409.
18. Wu DC, Teismann P, Tieu K, et al. NADPH oxidase mediatesoxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine model of Parkinson’s disease. Proc Natl Acad Sci USA 2003;100:6145–6150.
19. Hunot S, Boissiere F, Faucheux B, et al. Nitric oxide synthaseand neuronal vulnerability in Parkinson’s disease. Neuroscience1996;72:355–363.
20. Choi DK, Pennathur S, Perier C, et al. Ablation of the inflamma-tory enzyme myeloperoxidase mitigates features of Parkinson’sdisease in mice. J Neurosci 2005;25:6594–6600.
21. Teismann P, Tieu K, Choi DK, et al. Cyclooxygenase-2 is instru-mental in Parkinson’s disease neurodegeneration. Proc Natl AcadSci USA 2003;100:5473–5478.
22. Bas J, Calopa M, Mestre M, et al. Lymphocyte populations inParkinson’s disease and in rat models of parkinsonism. J Neuro-immunol 2001;113:146–152.
23. Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, et al.MHC class II positive microglia and lymphocytic infiltration arepresent in the substantia nigra and striatum in mouse model ofParkinson’s disease. Acta Neurobiol Exp (Wars) 1999;59:1–8.
24. Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, et al. Theinflammatory reaction following 1-methyl-4-phenyl-1,2,3, 6-tetra-hydropyridine intoxication in mouse. Exp Neurol 1999;156:50–61.
25. Benner EJ, Mosley RL, Destache CJ, et al. Therapeutic immuni-zation protects dopaminergic neurons in a mouse model of Par-kinson’s disease. Proc Natl Acad Sci USA 2004;101:9435–9440.
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Movement Disorders, Vol. 25, Suppl. 1, 2010