Autophagic Flux Bottlenecks in Neurodegenerative Disease: From Cell-Specific Failure to Defect-Directed Therapy

Autophagic dysfunction is a recurrent feature of neurodegenerative disease, but increased pathway activity does not necessarily indicate effective cargo clearance. This review examines autophagic flux as a multistep quality-control process in which cargo recognition, autophagosome formation, intracellular transport, lysosomal fusion, degradation, and metabolite recovery must remain functionally coupled. We discuss how bottlenecks at different stages generate distinct consequences across neurons, microglia, astrocytes, oligodendrocyte-lineage cells, and neural stem or progenitor cells, and compare disease-specific patterns in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis/frontotemporal dementia, Huntington’s disease, and multiple sclerosis. These disorders exhibit overlapping but context-dependent autophagy–lysosomal defects, including impaired cargo recognition, mitochondrial turnover, autophagosome transport, lysosomal degradation, and cell-specific cargo processing. These mechanistic differences support defect-directed therapeutic strategies, although evidence that correcting individual bottlenecks restores autophagic flux and improves clinical outcomes remains limited. Upstream induction may be ineffective when downstream transport, fusion, or lysosomal degradation is impaired. Therapeutic strategies should therefore be evaluated using mechanism-appropriate measures of target engagement and downstream cargo degradation. Defining autophagic flux at cell- and compartment-specific resolution may help distinguish productive clearance from nonspecific pathway activation across disease stages, genotypes, and clinically distinct patient populations.