Abstract
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.
Highlights
Lysosome axonal transport is important for the clearance of cargoes sequestered by the endocytic and autophagic pathways
The axonal plasma membrane is supported by an organized cytoskeletal network containing actin filaments and spectrin tetramers[12,28,29]
This actin-spectrin network, which has been linked to axonal mechanical stability[3,13] and signaling[30], was recently shown to undergo transient local expansion to facilitate the transport of large cargoes in narrow axons[31]
Summary
Lysosome axonal transport is important for the clearance of cargoes sequestered by the endocytic and autophagic pathways. 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. Primary cultures of mouse JIP3 knockout neurons exhibit a striking increase in the overall abundance of axonal lysosomes with focal accumulations within axonal swellings that are strikingly similar to the lysosome-filled axonal swellings observed at amyloid plaques[23] These changes raised questions about the relationship between lysosomes and the axonal cytoskeleton with potential implications for Alzheimer’s disease. Our observations support a model wherein perturbed axonal lysosome transport induced by loss of JIP3 (or JIP3 and JIP4) is closely linked to a broad disruption of the neuronal cytoskeleton
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