In familial neurodegenerative disorders, protein aggregates form continuously because of genetic mutations that drive the synthesis of truncated or unfolded proteins. The oxidative stress imposed by neurotransmitters and environmental neurotoxins constitutes an additional threat to the folding of the proteins and the integrity of organelle membranes in neurons. Failure in degrading such altered materials compromises the function of neurons and eventually leads to neurodegeneration. The lysosomal proteolytic enzyme Cathepsin D is the only aspartic-type protease ubiquitously expressed in all the cells of the human body, and it is expressed at high level in the brain. In general, cathepsin D mediated proteolysis is essential to neuronal cell homeostasis through the degradation of unfolded or oxidized protein aggregates delivered to lysosomes via autophagy or endocytosis. More specifically, many altered neuronal proteins that hallmark neurodegenerative diseases (e.g., the amyloid precursor, α-synuclein, and huntingtin) are physiologic substrates of cathepsin D and would abnormally accumulate if not efficiently degraded by this enzyme. Furthermore, experimental evidence indicates that cathepsin D activity is linked to the metabolism of cholesterol and of glycosaminoglycans, which accounts for its involvement in neuronal plasticity. This review focuses on the unique role of cathepsin D mediated proteolysis in the pathogenesis of human neurodegenerative diseases.

The ERCC8/CSA gene encodes a WD-40 repeat protein (CSA) that is part of a E3-ubiquitin ligase/COP9 signalosome complex. When mutated, CSA causes the Cockayne Syndrome group A (CS-A), a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. CS-A cells features include ROS hyperproduction, accumulation of oxidative genome damage, mitochondrial dysfunction and increased apoptosis that may contribute to the neurodegenerative process. In this study, we show that CSA localizes to mitochondria and specifically interacts with the mitochondrial fission protein dynamin-related protein (DRP1) that is hyperactivated when CSA is defective. Increased fission is not counterbalanced by increased mitophagy in CS-A cells thus leading to accumulation of fragmented mitochondria. However, when mitochondria are challenged with the mitochondrial toxin carbonyl cyanide m-chloro phenyl hydrazine, CS-A fibroblasts undergo mitophagy as efficiently as normal fibroblasts, suggesting that this process remains targetable to get rid of damaged mitochondria. Indeed, when basal mitophagy was potentiated by overexpressing Parkin in CSA deficient cells, a significant rescue of the dysfunctional mitochondrial phenotype was observed. Importantly, Parkin overexpression not only reactivates basal mitophagy, but plays also an anti-apoptotic role by significantly reducing the translocation of Bax at mitochondria in CS-A cells. These findings provide new mechanistic insights into the role of CSA in mitochondrial maintenance and might open new perspectives for therapeutic approaches.