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bioRxiv · 10.1101/2020.06.13.149443

Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons

Gowrishankar, S.·Lyons, L.·Rafiq, N. M.·Roczniak-Ferguson, A.·De Camilli, P.·Ferguson, S.
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Abstract

The dependence of neurons on microtubule-based motors for the movement of lysosomes over long distances raises questions about adaptations that allow neurons to meet these demands. Recently, JIP3/MAPK8IP3, a neuronally enriched putative adaptor between lysosomes and motors, was identified as a critical regulator of axonal lysosome abundance. In this study, we establish a human induced pluripotent stem cell (iPSC)-derived neuron model for the investigation of axonal lysosome transport and maturation and show that loss of JIP3 results in the accumulation of axonal lysosomes and the Alzheimers disease-related amyloid precursor protein (APP)-derived A{beta}42 peptide. We furthermore reveal an overlapping role of the homologous JIP4 gene in lysosome axonal transport. These results establish a cellular model for investigating the relationship between lysosome axonal transport and amyloidogenic APP processing and more broadly demonstrate the utility of human iPSC-derived neurons for the investigation of neuronal cell biology and pathology.

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Gowrishankar, S., Lyons, L., Rafiq, N. M., Roczniak-Ferguson, A., De Camilli, P., Ferguson, S.. 2020-06-13. Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons. https://doi.org/10.1101/2020.06.13.149443

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