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

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 Alzheimer's disease-related amyloid precursor protein (APP)-derived Aβ42 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.

Lysosome Function and Dysfunction in Hereditary Spastic Paraplegias

“…JIP3/MAPK8iP3 and its orthologs in nematode worms and zebrafish have been implicated in retrograde axonal lysosome transport [ 79 , 80 , 81 , 82 ]. In mammalian systems (mice and iPSC-derived neurons), loss of JIP3 leads to axonal swellings that are filled with lysosomes [ 81 , 82 ].…”

“…JIP3/MAPK8iP3 and its orthologs in nematode worms and zebrafish have been implicated in retrograde axonal lysosome transport [ 79 , 80 , 81 , 82 ]. In mammalian systems (mice and iPSC-derived neurons), loss of JIP3 leads to axonal swellings that are filled with lysosomes [ 81 , 82 ]. In the last two to three years, recurrent de novo variants of mapk8ip3 have been identified in individuals who manifest with mild to severe intellectual disability, hypoplasia of corpus callosum, and cerebral or cerebellar atrophy [ 83 ].…”

Optogenetic Tools for Manipulating Protein Subcellular Localization and Intracellular Signaling at Organelle Contact Sites

“…no. 9091) can be used for the efficient detection of lysosomes (Gowrishankar et al, 2020). Immunolabeling of the peroxisomal biogenesis protein PEX14 (Anti-PEX14, Millipore GmbH, cat.…”

JIP4 is recruited by the phosphoinositide-binding protein Phafin2 to promote recycling tubules on macropinosomes

“…Phafin2 does not interact with JIP3, nor does Phafin1 bind to JIP4. This is important to note, since several other studies have proposed that JIP3 and JIP4 have overlapping functions, and some phenotypes are reported under double knockdown or knockout conditions (Boecker et al, 2021;Gowrishankar et al, 2020;Marchesin et al, 2015;Sato et al, 2015;Vilela et al, 2019b;Williamson & Donaldson, 2019). In comparative structural and biochemical analysis, the similarity of the first two coiled-coil regions has been noted (Isabet et al, 2009;Williamson & Donaldson, 2019).…”