Pink1 brings to five the total number of genes that are known to cause Parkinson’s disease or parkinsonism when mutated, the other four being α -synuclein, parkin, Uch-L1, and DJ-1. The last, once known as PARK7, was identified just over a year ago (see ARF related news story).

First author Enza Maria Valente and colleagues traced the origin of the PARK6 locus by mapping mutations in affected families from Sicily, central Italy, and Spain, homing in on a small region of chromosome 1. The authors then analyzed individual genes in the location. They found that affected members of the families had homozygous mutations in either of two loci, both in Pink1. Members of the Spanish family carried a simple guanine-to-adenine transition in exon 4 of the gene, while both Italian families were affected by a similar G-to-A transition in exon 7.

Pink1 is a 581 amino acid protein with a mitochondrial signal sequence. It has homology to serine/threonine kinases, which helps explain why the mutations are so devastating. When the authors compared Pink1 with other kinases, they found that the exon 4 mutation replaces a highly conserved glycine in the kinase domain with aspartic acid, while the exon 7 mutation, which results in premature termination of the protein, completely abolishes the C-terminus of the same domain.

But what does Pink1 do? It may be necessary to maintain the electrical balance across the mitochondrial membrane, suggest the authors. When Valente and colleagues stressed mitochondria expressing the exon 4 mutant, they found that the membrane potential decreased by 44 percent, whereas that of wild-type mitochondria fell by only 8 percent under the same conditions. They also found that wild-type Pink1 can protect cells against mitochondrial-induced apoptosis, whereas the mutant could not.

These findings add significantly to a growing body of literature on the role of mitochondria in Parkinson’s. While mitochondrial toxins are known to cause neurodegeneration and are widely used to mimic Parkinson’s in animal models, a direct link between these organelles and familial Parkinson’s disease has been lacking. Recently, it was shown that mutations in parkin can have global effects on mitochondrial protein expression and activity (see ARF related news story and ARF news story). The identification of Pink1 as a Parkinson’s gene will no doubt steel those who have been focusing on the mitochondrial connection. Incidentally, the same issue of Science magazine also carries a report on a mitochondrial enzyme that interacts specifically with Aβ, supporting the widely held assumption that an inability of mitochondria to handle cell stress may be a general but important factor that interacts with disease-specific molecules to cause Parkinson’s in one person and AD in another.—Tom Fagan.

Reference:
Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1. Science. 2004 Apr 15 [Epub ahead of print] Abstract