Metabolic and differentiation impairment in Parkinson?s Disease patient-derived iPSCs with a triplication event including the SNCA locus

FALOMIR LOCKHART LJ

Buenos Aires

Congreso; II FALAN Congress; 2016

Sociedad Argentina de Neurociencias

Parkinson?s disease (PD) is the 2nd most common neurodegenerative disorder. Its pathologic hallmark is the functional loss of dopaminergic neurons and the appearance of intracellular amyloid aggregates, constituted mainly by α-Synuclein (aSyn) protein. Although most PD cases are sporadic, mutations are known and usually correlated with early onset. We studied metabolic changes and neuronal differentiation of induced Pluripotent Stem-like cells (iPSCs) that were derived from patients with a triplication of the SNCA gene (SNCAx3) and age-matched healthy controls under normal and environmentally stressed conditions to model in vitro gene-environment interactions which may play a role in the initiation and progression of PD.The iPSCs lines were initially committed to a neuronal linage, where SNCAx3 cells showed impaired viability, energetic metabolism and stress resistance to starvation and toxicants. A two-steps differentiation protocol was then employed to obtain neurons. SNCAx3 cells exhibited a delayed and decreased capacity to differentiate into neurons. Differentiated SNCAx3 cells showed decreased neurite outgrowth and lower electrophysiological activity. Knockdown by shRNAi against aSyn systematically and significantly ameliorated SNCAx3 defects. Results suggest a two-fold aSyn overexpression is sufficient to set the stage for decreased developmental fitness, accelerated aging, impaired neuronal differentiation and increased neuronal cell loss.