Gaucher Disease (GD) is the most common Lysosomal Storage Disorder and results from mutations in the glucocerebrosidase (GBA) gene. Loss of functional GBA in lysosomes leads to accumulation of glucocerebroside, resulting in non-functional organelles. This has far reaching implications in autophagy, where lysosomes fuse with autophagosomes to degrade unwanted/damaged cellular material. Strong evidence has emerged linking lysosomal dysfunction and Parkinson’s Disease (PD); individuals with a homozygous loss of GBA have up to a twenty fold increased risk of developing PD, thus loss of GBA activity is the highest genetic risk factor for PD.

Using a murine model of type II neuropathic GD, gba^-/- primary neurons and astrocytes have a defective autophagy pathway with reductions in LC3-I/II and Atg5/12 levels, suggestive of a negative feedback loop upstream of lysosomal involvement. Defective autophagy impinges on the ubiquitin-proteasome system with increases in ubiquitinated proteins, p62/SQSTM1 aggregates as well as α-synuclein deposits in the midbrain. As a result of defective quality control mechanisms dysfunctional mitochondria, that are unable to recruit the E3 ubiquitin ligase Parkin, are not flagged for turnover and accumulate. gba^-/-cells have reductions in CI, CII/III activity and membrane potential (ΔΨ_m) and hydrolyse ATP in order to maintain it. This coincides with mitochondrial fragmentation due to increased OPA1 processing. Loss of ΔΨ_m is rescued by the antioxidant MitoQ₁₀, suggesting damage is mediated by ROS generation from CI. In addition treatment with MitoQ₁₀ does not restore defects in the autophagy pathway, confirming a primary lysosomal defect affects cellular quality control. Taken together these findings suggest that cellular dysfunction observed in GD, like that of PD, is a consequence of defects in autophagy/mitophagy pathways, resulting in failed clearance of damaged mitochondria.