Description:

Silke Nuber, PhD
Brigham and Women's Hospital
Harvard Medical School, Department of Neurology
Cambridge, Massachusetts

Intraneuronal aggregates of α-synuclein (αSyn) characterize Parkinson's disease (PD), dementia with Lewy bodies (DLB) and related synucleinopathies. The disruption in αSyn proteostasis is a critical step for neurotoxicity, however, the mechanisms preceding aggregation as well as the resultant cytotoxic species are yet not clarified. The loss of native tetramers and C-terminal truncation of accumulating monomers via the calcium-dependent protease calpain can facilitate the conversion of physiologic αSyn into pathological aggregates. Using environmental toxins and novel tetramer-abrogating mutant mice, we hypothesize a central role of calpain-mediated synucleinopathy in both familial and sporadic PD.