Drug targets from genetics: ?-synuclein.

ABSTRACT: One of the critical issues in Parkinson disease (PD) research is the identity of the specific toxic, pathogenic moiety. In PD, mutations in ?-synuclein (?syn) or multiplication of the SNCA gene encoding ?syn, result in a phenotype of cellular inclusions, cell death, and brain dysfunction. While the historical point of view has been that the macroscopic aggregates containing ?syn are the toxic species, in the last several years evidence has emerged that suggests instead that smaller soluble species--likely oligomers containing misfolded ?syn--are actually the toxic moiety and that the fibrillar inclusions may even be a cellular detoxification pathway and less harmful. If soluble misfolded species of ?syn are the toxic moieties, then cellular mechanisms that degrade misfolded ?syn would be neuroprotective and a rational target for drug development. In this review we will discuss the fundamental mechanisms underlying ?syn toxicity including oligomer formation, oxidative stress, and degradation pathways and consider rational therapeutic strategies that may have the potential to prevent or halt ?syn induced pathogenesis in PD.

SUBMITTER: Danzer KM 

PROVIDER: S-EPMC3364517 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature