Gaucher disease, the most common
lysosomal storage disease, is caused by a recessively inherited deficiency in
glucocerebrosidase and subsequent accumulation of toxic
lipid substrates. Heterozygous mutations in the lysosomal
glucocerebrosidase gene (GBA1) have recently been recognized as the highest genetic risk factor for the development of α-
synuclein aggregation disorders ("
synucleinopathies"), including
Parkinson's disease (PD) and
dementia with Lewy bodies (DLB). Despite the wealth of experimental, clinical and genetic evidence that supports the association between mutant genotypes and
synucleinopathy risk, the precise mechanisms by which GBA1 mutations lead to PD and DLB remain unclear. Decreased
glucocerebrosidase activity has been demonstrated to promote α-
synuclein misprocessing. Furthermore, aberrant α-
synuclein species have been reported to downregulate
glucocerebrosidase activity, which further contributes to
disease progression. In this review, we summarize the recent findings that highlight the complexity of this pathogenetic link and how several pathways that connect
glucocerebrosidase insufficiency with α-
synuclein misprocessing have emerged as potential therapeutic targets. From a translational perspective, we discuss how various therapeutic approaches to lysosomal dysfunction have been explored for the treatment of GBA1-related
synucleinopathies, and potentially, for non-GBA1-associated
neurodegenerative diseases. In summary, the link between GBA1 and
synucleinopathies has become the paradigm of how the study of a rare lysosomal disease can transform the understanding of the etiopathology, and hopefully the treatment, of a more prevalent and multifactorial disorder.