Unravelling a mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in MPS VII

Progressive neurodegeneration and cognitive disability are prominent symptoms of MPS VII, a lysosomal storage disorder caused by β-glucuronidase enzyme deficiency. Yet, the mechanism of neurodegeneration in MPS VII remains elusive thereby limiting the scope of targeted intervention. To address this, we recently developed a β-glucuronidase-deficient (CG2135 ^-/- ) Drosophila model of MPS VII. The CG2135 ^-/- flies exhibited signs of neuromuscular degeneration, including loss of dopaminergic neurons, and accumulated engorged lysosomes, ubiquitinated proteins and mitochondria in their brains. These observations, coupled with our current finding that the CG2135 ^-/- flies were highly susceptible to starvation, prompted us to investigate potential defects in the autophagy-lysosomal clearance machinery in the brain. We found that both autophagy induction and lysosome-mediated autophagosomal turnover were impaired in the CG2135 ^-/- fly brain. This was evidenced by lower Atg8a-II levels, reduced Atg1 and Ref(2)P expression along with accumulation of lipofuscin-like inclusions and multilamellar bodies. Interestingly, mitophagy was also found to be defective in their brain, causing buildup of enlarged mitochondria with distorted cristae and reduced membrane potential. This, in turn, affected mitochondrial function as reflected by drastically reduced brain ATP levels. Energy depletion triggered apoptosis in neuronal as well as non-neuronal cells of the CG2135 ^-/- fly brain, where we also detected apoptotic dopaminergic neurons. Resveratrol treatment, previously found to protect against loss of dopaminergic neurons in the CG2135 ^-/- flies, has now been shown act by correcting the mitophagy defect and preventing ATP depletion. Collectively, our study establishes a causal link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in MPS VII.