Glucocerebrosidase deficiency appears to be associated with increased α-synuclein aggregation and accumulation, mitochondrial dysfunction because of impaired autophagy, and increased endoplasmic reticulum stress.
Our results suggest that GBA deficiency due to L444P GBA heterozygous mutation and the accompanying accumulation of α-synuclein render DA neurons more susceptible to MPTP intoxication.
These findings demonstrate that loss of GBA function may contribute to SNCA accumulation through inhibition of autophagy via PPP2A inactivation, thereby providing a mechanistic basis for the increased PD risk associated with GBA deficiency.
Glucocerebrosidase deficiency accelerates the accumulation of proteinase K-resistant α-synuclein and aggravates neurodegeneration in a Drosophila model of Parkinson's disease.