Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson's Disease.

ABSTRACT: α-Synuclein (αS) regulates vesicle exocytosis but forms insoluble deposits in Parkinson's disease (PD). Developing disease-modifying therapies requires animal models that reproduce cardinal features of PD. We recently described a previously unrecognized physiological form of αS, α-helical tetramers, and showed that familial PD-causing missense mutations shift tetramers to aggregation-prone monomers. Here, we generated mice expressing the fPD E46K mutation plus 2 homologous E→K mutations in adjacent KTKEGV motifs. This tetramer-abrogating mutant causes phenotypes similar to PD. αS monomers accumulate at membranes and form vesicle-rich inclusions. αS becomes insoluble, proteinase K-resistant, Ser129-phosphorylated, and C-terminally truncated, as in PD. These changes affect regions controllin

SUBMITTER: Nuber S 

PROVIDER: S-EPMC6211795 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature