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 perturbations result in neurodegeneration is unclear. Neuronopathic lysosomal storage disorders represent an attractive model for elucidating such mechanisms as they share several metabolic pathological hallmarks with common neurodegenerative diseases. This review explores how altered lipid metabolism, calcium dyshomeostasis, mitochondrial dysfunction, 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 substrate accumulation or extralysosomal nutrient deprivation drives these downstream processes. With increasing evidence for the latter, future studies should investigate additional lysosomal nutrients that protect against neurodegeneration using emerging subcellular ‘omics’-based technologies with the promise of identifying therapeutic targets for the treatment of neurodegenerative diseases.