• Alpha-synuclein
• Gaucher’s disease
• Gba1
• glucocerebrosidase
• L444P
• neurodegeneration
• Parkinson’s disease
• prion

Alpha-synuclein (αS) is a pre-synaptic protein which, in pathological conditions, acquires the tendency to aggregate, giving rise to toxic oligomers that ultimately lead to Parkinson’s disease (PD) and other α-synucleinopathies. The toxic effects of oligomers can be summarized as the Parkinsonian triad, that is the impairment of the mitochondria, proteostasis and endoplasmic reticulum. In turn, the triad determines synaptic impairment, and promotes further oligomerization of αS.

A bidirectional relationship exists between the impairment of the lysosomal enzyme glucocerebrosidase (GCase) and the accumulation of αS. Whereas homozygous impairments in the GCase gene (Gba1) are causative for Gaucher’s Disease, heterozygous impairments are epidemiologically the most common genetic risk factor for PD and DLB, with an odds ratio of 5.1, and 10-30% of carriers developing PD after 80 years of age.

This project provides a novel systematic characterization of the Gba1 KO/+ and L444P/+ phenotypes. The results suggest that a heterozygous GCase impairment produces a “slight and slow” αS accumulation that is already in the pathological conformation, so that any externally-induced or stochastic increase in αS becomes exacerbated, rapidly leading to overt α-synucleinopathy.