GBA1 mutations as a role model for precision medicine in Parkinson’s disease

Abstract

Genetic variants in GBA1 , encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the strongest genetic risk factor for Parkinson’s disease (PD) and provide a mechanistic link between Gaucher disease (GD) and PD. While biallelic GBA1 mutations cause GD, heterozygous variants confer an increased, age-dependent risk of PD, with mutation-specific differences in penetrance, age at onset, cognitive decline, and survival. This review critically examines the molecular and clinical spectrum of GBA1 -associated PD (GBA1-PD), highlighting the relationship between variant severity, lysosomal dysfunction, and disease progression. We discuss two major, partially overlapping pathogenic frameworks underlying GBA1 -PD: loss-of-function mechanisms associated with reduced GCase activity, glycosphingolipid accumulation, and impaired autophagy–lysosomal pathways, and toxic gain-of-function mechanisms driven by mutant GCase misfolding, endoplasmic reticulum stress, and proteostatic imbalance. Increasing evidence suggests that these mechanisms converge on α-synuclein aggregation and dopaminergic neurodegeneration. We further summarize emerging disease-modifying therapeutic strategies, including small-molecule GCase activators, pharmacological chaperones, substrate reduction therapies, acid ceramidase inhibitors, and gene therapies. Although clinical outcomes have been heterogeneous, GBA1 -associated PD represents a valuable model for precision medicine, illustrating how genetic stratification can guide mechanism-based therapeutic development in neurodegeneration.