A genetic screen for Parkinson’s susceptibility

Why are some individuals more susceptible than others to age-related neurodegeneration, such as Parkinson’s disease (PD)? Many major players have been identified: we now know, for example, that misfolding and aggregation of the alpha-synuclein protein contributes substantially to the degeneration of dopaminergic neurons. Genomic amplification of the alpha-synuclein gene contributes to increased risk of PD, probably because more protein means more chances for aggregates to form — the world’s worst lottery.

Most PD patients, however, do not exhibit structural polymorphisms at the alpha-synuclein locus — but they are still likely to possess genetic variants that increase their vulnerability to the disease. These variations run in families, but the genetics are abominably hard: each variant may contribute only a tiny amount to disease risk, but risk is hard to measure — we can only really be sure whether or not a given individual has developed the disease. If we’re lucky enough to have a large pedigree to analyze, we might be able to back-calculate the risk contributions of individual loci, but (a) this is screamingly hard, and (b) the analysis is confounded by the incidence of sporadic disease (i.e., PD that occurs for some reason other than genetic factors).

Therefore, classical genetics in model organisms still holds tremendous value as a means of identifying susceptibility loci for PD and other late-life degenerative illnesses. Hamamichi et al. have performed a screen for worm mutants that misfold alpha-synuclein, and identified 20 genes involved in this process; they infer that the wildtype genes protect against alpha-synuclein aggregation and thereby against degeneration of dopaminergic neurons.

Because the worm allows for full knockdown of gene function (here as a result of RNA interference), the authors were able to observe clear phenotypes rather than the small increases in risk that would result from minor functional variations between polymorphic alleles. Consequently, they were able to identify genes involved in alpha-synuclein processing that would have been difficult or impossible to catch in studies of human populations. The human homologs of the worm genes will be excellent candidates for PD susceptibility loci in the human population, as well as targets for pharmacological intervention.

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