Lysosomes as chemical and metabolic organizers of central nervous system injury and repair

Abstract

Lysosomes are degradative, metabolic and signaling organelles in central nervous system (CNS) cells and play essential roles in neural homeostasis, injury responses and disease progression. Changes in lysosomal function are required for neurons, microglia, astrocytes and oligodendrocyte-lineage cells to adapt to proteotoxic stress, lipid overload, mitochondrial damage and inflammatory stimulation. Therefore, lysosomal activity in the CNS is regulated by diverse chemical and cellular cues, including luminal acidification, hydrolase maturation, ion transport, membrane integrity, lipid handling and transcriptional lysosome biogenesis. Here, we summarize current knowledge of lysosomal organization and function in neural cells, including lysosomal membrane signaling, vacuolar H + -ATPase (V-ATPase)-dependent acidification, ion and redox regulation, lysosomal membrane quality control, and metabolic recycling of proteins, lipids, glycans and damaged organelles. We then survey pathological lysosomal remodeling in spinal cord injury, traumatic brain injury, Alzheimer’s disease, Parkinson’s disease and related neurological disorders. Across these conditions, lysosomal remodeling may initially support cargo clearance and stress adaptation, but becomes maladaptive when degradative capacity, membrane repair or lipid-processing ability fails to meet cellular demand. Finally, we discuss lysosome-oriented therapeutic strategies for neural repair, including restoration of lysosomal acidification and hydrolase activity, transcription factor EB/transcription factor E3 (TFEB/TFE3)-mediated lysosomal biogenesis, regulation of lysosomal ion channels, enhancement of myelin lipid turnover, and lysosome-responsive nanomedicine. This Review highlights lysosomes as active organizers of CNS injury and repair rather than passive endpoints of degradation.