Glucocerebrosidase Activity Modulates Neuronal Susceptibility to Pathological α-Synuclein Insult

Mutations in the GBA1 gene are the most common genetic risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). GBA1 encodes the lysosomal lipid hydrolase glucocerebrosidase (GCase), and its activity has been linked to accumulation of α-synuclein. The current study systematically examines the relationship between GCase activity and both pathogenic and non-pathogenic forms of α-synuclein in primary hippocampal, cortical, and midbrain neuron and astrocyte cultures, as well as in transgenic mice and a non-transgenic mouse model of PD. We find that reduced GCase activity does not result in aggregation of α-synuclein. However, in the context of extant misfolded α-synuclein, GCase activity modulates neuronal susceptibility to pathology. Furthermore, this modulation does not depend on neuron type but rather is driven by the level of pathological α-synuclein seeds. This study has implications for understanding how GBA1 mutations influence PD pathogenesis and provides a platform for testing novel therapeutics. [Display omitted] •GCase inhibition does not lead to α-synuclein aggregation in cell or animal models•Reducing GCase activity enhances pre-existing α-synuclein aggregation•GCase modulation of α-synuclein aggregation does not depend on neuron type•GCase activity enhances α-synuclein pathology when pathological seeds are low Henderson et al. use cell and animal models of Parkinson’s disease to show that reducing glucocerebrosidase activity leads to an enhancement of pre-existing α-synuclein pathology that does not depend on neuron type, reconciling experimental biology with human epidemiology.