Lessons from metabolic perturbations in lysosomal storage disorders for neurodegeneration

Age-related neurodegenerative diseases are a clinically unmet need with unabated prevalence around the world. Several genetic studies link these diseases with lysosomal dysfunction; however, a mechanistic understanding of how lysosomal per-turbations result in neurodegeneration is unclear. Neuro-nopathic lysosomal storage disorders represent an attractive model for elucidating such mechanisms as they share several metabolic pathological hallmarks with common neurodegen-erative diseases. This review explores how altered lipid metabolism, calcium dyshomeostasis, mitochondrial dysfunc-tion, oxidative stress, and impaired autophagic flux contribute to cellular pathobiology in age-related neurodegeneration and neuronopathic lysosomal storage disorders. It further debates whether general lysosomal dysfunction owing to toxic sub-strate accumulation or extralysosomal nutrient deprivation drives these downstream processes. With increasing evidence for the latter, future studies should investigate additional lyso-somal nutrients that protect against neurodegeneration using emerging subcellular ???omics???-based technologies with the promise of identifying therapeutic targets for the treatment of neurodegenerative diseases.