Molecular mechanisms of α-synuclein and GBA1 in Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized pathologically by the presence of Lewy bodies comprised of insoluble alpha (α)-synuclein. Pathological, clinical and genetic studies demonstrate that mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase) that is deficient in Gaucher's disease, are important risk factors for the development of PD. The molecular mechanism for the association between these two diseases is not completely understood. We discuss several possible mechanisms that may lead to GBA1-related neuronal death and α-synuclein accumulation including disruptions in lipid metabolism, protein trafficking and impaired protein quality control mechanisms. Elucidating the mechanism between GCase and α-synuclein may provide insight into potential therapeutic pathways for PD and related synucleinopathies.

Keywords: Alpha (α)-synuclein; Glucosylceramide; Lysosomal dysfunction; Neurodegeneration; Protein aggregation.

Figure 1

Potential gain- and loss-of-function mechanisms for the role of GBA1 pathogenesis in PD. (a) Misfolded mutant GCase (e.g. N370S, L444P) in the ER causes ER stress and may lead to a-syn aggregation and inhibition of ER-to-Golgi protein trafficking. (b) Loss of GCase function leads to accumulation of lipids such as GluCer, which directly interacts with and stabilizes a-syn oligomers in the lysosomal compartment. The consequent a-syn accumulation inhibits ER-to-Golgi GCase trafficking, resulting in a positive feedforward loop of self-propagating disease. Loss of GCase function may also cause general lysosomal dysfunction, defective mitophagic and autophagic clearance pathways, and Ca²⁺ homeostasis dysfunction. Potential for therapeutic interventions involving multiple pathways are being explored such as ER, trafficking machinery, reduced GluCer synthesis, and direct activation of GCase within lysosomes.