Newsdesk

560 http://neurology.thelancet.com Vol 5 July 2006

Mitochondrial PINK1–PARK2 problem may promote PD

Experiments with drosophila suggest that mutation of the human PINK1 gene could lead to Parkinson’s disease (PD) via the impairment of mitochondrial function (Nature 2006, published online May 3. DOI:10.1038/nature04779 and DOI:10.1038/nature04788). These fi ndings, released by two independent groups, add to the growing evidence that mitochondrial dysfunction is central to the develop-ment of Parkinson’s disease.

“Mutations in PINK1 and parkin [PARK2] have been associated with familial, early onset and sporadic forms of PD”, explains Ming Guo (University of California, Los Angeles, USA). “In addition, PD has been linked to mitochondrial dysfunction since exposure to mitochondrial toxins leads to PD-like pathology.

The observations reported in these two new papers help link all this together by showing that mutations in pink1, the drosophila analogue of human PINK1, can lead to mitochondrial dysfunction and even the degeneration of dopaminergic neurones.”

Guo’s team generated drosophila pink1-deletion strains and examined the morphology of their mitochondria (where the pink1 product localises). The energy-intensive fl ight muscles were disorganised and the mitochondrial cristae either fragmented or virtually absent. “These muscle problems were degenerative in nature since they were not appreciable when the fl ies fi rst hatched”, explains Guo.

In further experiments the team also showed that the pink1-deletion mutants were more sensitive to free radicals. The inability to tolerate free radicals is a known problem of mitochondrial dysfunction—and free radical damage has been associated with PD, further linking the disease to PINK1 mutations in human beings.

In independent work, researchers led by Jongkyeong Chung (Korea Advanced Institute of Science and Technology, Taejon, Korea) obtained similar results. Their drosophila pink1 mutants also had fl ight-muscle defects, a probable result of the marked reduction in their mitochondrial DNA load.

Importantly, Chung’s team also saw evidence of mitochondrial dysfunction

in the dopaminergic neurons of Pink1 mutant brains. “Since dopaminergic neurodegeneration is the most critical issue in Parkinson’s disease, we examined the morphology of the mitochondria in dopaminergic neurons using TEM and [via the expression of green fl uorescent protein]”, explains Chung. Many were enlarged, a condition that seemed to correlate with both reduced dopamine concentrations and neurodegeneration; adult pink1 mutant fl ies showed a 10% loss of dopaminergic neurons.

“It therefore seems likely that human PINK1 is involved in maintaining mitochondrial integrity: without it the mitochondria become dysfunctional, leading to a range of factors linked to PD.”

Both teams also report pink1 and parkin almost certainly belong to the same pathway. Parkin overexpression compensated for the lack of pink1, suggesting that the product of pink1 functions upstream of parkin.

Doug Turnbull (University of Newcastle, UK), commented: “Working out the full pathway via which PINK1 and parkin are involved in maintaining mitochondrial integrity might show a point where we could act to halt mitochondrial breakdown and hopefully help us prevent and treat PD—at least in patients with mutations in these genes.”

Adrian Burton

New ligands for the old neurotrophin receptorThe nerve growth factor family of neurotrophins targets two kinds of transmembrane receptors: the receptor tyrosine kinases (Trk A, B, and C), and p75. This latter protein, initially characterised in the 1980s, was, for many years, believed to work as a modulator of the Trk receptors. However, evidence is mounting for

p75’s many roles in determining the life and death of nerve cells, independently of Trks. Depending on the type of cell, “p75 can promote neuronal survival, induce apoptosis, promote myelination, regulate neurite outgrowth”, explains Bruce Carter (Vanderbilt University, Nashville, USA). In a new study, Steve Massa (University

of California at San Francisco, USA), Frank Logo (UNC, Chapel Hill, USA), and collaborators have identifi ed the fi rst small non-peptide ligands that work exclusively through p75, and not the Trk receptors. These compounds, named “LM11As”, can help to detangle p75-mediated signalling networks, and are promising drug candidates, the

Drosophila experiments shed light on mitochondrial dysfunction in PD

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