Mitochondria and Quality Control Defects in a Mouse Model of Gaucher Disease—Links to Parkinson’s Disease

Abstract

SummaryMutations in the glucocerebrosidase (gba) gene cause Gaucher disease (GD), the most common lysosomal storage disorder, and increase susceptibility to Parkinson’s disease (PD). While the clinical and pathological features of idiopathic PD and PD related to gba (PD-GBA) mutations are very similar, cellular mechanisms underlying neurodegeneration in each are unclear. Using a mouse model of neuronopathic GD, we show that autophagic machinery and proteasomal machinery are defective in neurons and astrocytes lacking gba. Markers of neurodegeneration—p62/SQSTM1, ubiquitinated proteins, and insoluble α-synuclein—accumulate. Mitochondria were dysfunctional and fragmented, with impaired respiration, reduced respiratory chain complex activities, and a decreased potential maintained by reversal of the ATP synthase. Thus a primary lysosomal defect causes accumulation of dysfunctional mitochondria as a result of impaired autophagy and dysfunctional proteasomal pathways. These data provide conclusive evidence for mitochondrial dysfunction in GD and provide insight into the pathogenesis of PD and PD-GBA.

Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

“…These findings suggest that the Gba L444P/WT mutation impedes both PRKN/PARK2-dependent and -independent mitochondrial priming under basal conditions. Our data corroborate the Osellame et al study [10] where it was proposed that that MMP in gba knockout neurons was not low enough for PARK2 recruitment because mitophagy could be enhanced by fully dissipating MMP [10]. We thus concluded that mitochondria in Gba L444P/WT heterozygous mutant mice are compromised, and not flagged properly for turnover by the mitophagy pathway.…”

“…Given that hemizygous GBA WT/- cells do not show mitochondrial defects [10], we propose that mitochondrial phenotypes in GBA heterozygous mutants may require alternative mechanisms that involve the presence of mutant GBA protein. To distinguish the effect of mutant protein from the loss of GBA enzyme activity, we generated SH-SY5Y cells stably overexpressing MYC-tagged WT or L444P GBA on the background of both copies of endogenous WT GBA alleles.…”

“…Recent studies reported both mitochondrial dysfunction and autophagy defects in gba gene knockout GD mouse models and cell cultures [10,11,38,39], suggesting a loss-of-function mechanism of GBA mutations in mitochondrial dysfunction that is associated with GD. It remains unclear, however, whether and how PD-associated heterozygous GBA mutations contribute to mitochondrial dysfunction.…”

“…Recent studies reported mitochondrial fragmentation, reduced respiratory chain complex activities, decreased mitochondrial membrane potential (MMP) and lower oxygen consumption in neuronal and glial cells of Gba conditional knockout mice [9,10]. The link between GBA deficiency and mitochondrial dysfunction is corroborated by decreased MMP in neuronal cultures treated with conduritol B epoxide (CBE), a covalent inhibitor of GBA [11,12].…”

“…Whereas reduced GBA activity is associated with GBA1 mutations, and has been reported in both sporadic PD and heterozygous GBA-PD patients, as well as in D409V/WT, L444P/WT, and N370S/WT heterozygous GBA mutant or heterozygous Gba knockout (WT/-) mouse brain [13,14], hemizygous Gba knbockout ( Gba WT/- ) mouse neurons and glia do not show mitochondrial defects [10]. It thus remains unclear whether and how heterozygous GBA mutations, particularly those commonly encountered in PD patients (L444P and N370S), contribute to mitochondrial dysfunction associated with PD.…”