JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton

Rafiq et al. report that disruption of JIP3-dependent control of axonal lysosome transport in human neurons results in unexpected changes to the organization of multiple cytoskeletal proteins. This study provides new insights that improve our understanding of intellectual disabilities caused by mutations in JIP3, and are relevant for neurodegenerative diseases associated with accumulations of lysosomes such as the Alzheimer's disease Lysosome axonal transport is important for the clearance of cargoes sequestered by the endocytic and autophagic pathways. Building on observations that mutations in the JIP3 (MAPK8IP3) gene result in lysosome-filled axonal swellings, we analyzed the impact of JIP3 depletion on the cytoskeleton of human neurons. Dynamic focal lysosome accumulations were accompanied by disruption of the axonal periodic scaffold (spectrin, F-actin and myosin II) throughout each affected axon. Additionally, axonal microtubule organization was locally disrupted at each lysosome-filled swelling. This local axonal microtubule disorganization was accompanied by accumulations of both F-actin and myosin II. These results indicate that transport of axonal lysosomes is functionally interconnected with mechanisms that control the organization and maintenance of the axonal cytoskeleton. They have potential relevance to human neurological disease arising from JIP3 mutations as well as for neurodegenerative diseases associated with the focal accumulations of lysosomes within axonal swellings such as Alzheimer's disease.

Automated summary

Disruption of JIP3-dependent control of axonal lysosome transport in human neurons results in changes to the organization of multiple cytoskeletal proteins. This study improves our understanding of intellectual disabilities caused by mutations in JIP3 and is relevant for neurodegenerative diseases associated with lysosome accumulations such as Alzheimer's disease.