GBA1 Gene Mutations in alpha-Synucleinopathies-Molecular Mechanisms Underlying Pathology and Their Clinical Significance

alpha-Synucleinopathies comprise a group of neurodegenerative diseases characterized by altered accumulation of a protein called alpha-synuclein inside neurons and glial cells. This aggregation leads to the formation of intraneuronal inclusions, Lewy bodies, that constitute the hallmark of alpha-synuclein pathology. The most prevalent alpha-synucleinopathies are Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). To date, only symptomatic treatment is available for these disorders, hence new approaches to their therapy are needed. It has been observed that GBA1 mutations are one of the most impactful risk factors for developing alpha-synucleinopathies such as PD and DLB. Mutations in the GBA1 gene, which encodes a lysosomal hydrolase beta-glucocerebrosidase (GCase), cause a reduction in GCase activity and impaired alpha-synuclein metabolism. The most abundant GBA1 gene mutations are N370S or N409S, L444P/L483P and E326K/E365K. The mechanisms by which GCase impacts alpha-synuclein aggregation are poorly understood and need to be further investigated. Here, we discuss some of the potential interactions between alpha-synuclein and GCase and show how GBA1 mutations may impact the course of the most prevalent alpha-synucleinopathies.