28 Jun 2001

The two most prominent genes linked to inherited, monogenic Parkinson's disease-α-synuclein and parkin-are generally thought to be unconnected to each other because the forms of PD they cause are clinically and neuropathologically different. Yet in an article posted today on Science Express (http://www.sciencexpress.org), co-first authors Hideki Shimura and Michael Schlossmacher, working with Dennis Selkoe and Kenneth Kosik at Harvard Medical School's Center for Neurologic Diseases, report that the two proteins interact in a biochemical reaction. Moreover, they suggest that this reaction may underlie the aggregation of α-synuclein in conventional PD as well.

Their work centers on protein degradation. In this cascade of events, a series of enzymes dubbed E1, E2, and E3 activate and attach a chain of ubiquitin proteins to a substrate, tagging it for destruction in the proteasome. Last year Shimura et al. had shown parkin to be an E3 ligase. This and other findings raised the possibility that wildtype parkin might ubiquitinate α-synuclein, and that disease-linked mutations in parkin prevent this step toward the protein's proper disposal, said Schlossmacher. (α-synuclein is the abundant brain protein present in the neuronal "Lewy body" inclusions that characterize the most common, idiopathic form of PD.)

The paper reports four experiments supporting this idea. The authors found that α-synuclein and parkin co-localize in Lewy bodies of PD patients. They immunoprecipitated a protein complex from normal human brain, which contains parkin, an associated E2 enzyme, and a new, glycosylated form of α-synuclein (α-Sp22) as parkin's substrate. Next, the authors found that this brain-derived parkin specifically ubiquitinates α-Sp22 whereas mutant parkin from patients does not. Finally, the authors report that non-ubiquitinated α-Sp22 accumulated in parkin-deficient brains.

These findings suggest a hypothetical model to explain how inherited and sporadic forms of PD might arise from different alterations of the same underlying metabolic pathway, says Schlossmacher. In this view, loss of parkin would lead to accumulation of α-Sp22, which does not aggregate but might be neurotoxic. These patients do not have Lewy bodies but do have early onset of symptoms. In conventional PD, functioning parkin ubiquitinates α-Sp22 but subsequently, insufficient degradation would lead to a more gradual accumulation of polyubiquitinated α-Sp22, which tends to aggregate. These patients have Lewy bodies and late onset of symptoms.

The authors note that their data parallel findings reported in 1999 by Huda Zoghbi's group on the pathogenesis of polyglutamine expansions in the ataxin-1 gene. Mice expressing this mutated gene develop neuronal inclusions. When bred to lack the ataxin-1-specific E3 ligase, however, they show fewer inclusions but more severe neurodegeneration.—Gabrielle Strobel