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

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.

Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis

“…This was further supported by the observation that Jip3 knockout (KO) mouse dystrophic axons contain immature lysosomes with low levels of proteases, representing a population of lysosomal intermediates distinct from mature lysosomes in the cell body ( Gowrishankar et al, 2017 ). Interestingly, these axonal organelle accumulations were also observed in JIP3 KO human induced pluripotent stem cell–derived neurons, which were accompanied by disruptions in the axonal cytoskeleton and worsened by KO of homologous JIP4 ( Gowrishankar et al, 2021 ; Rafiq et al, 2022 ). JIP4 was previously characterized in nonneuronal cells as a dynein adaptor recruited to lysosomes through the lysosomal integral membrane protein TMEM55B ( Willett et al, 2017 ).…”

AP-4 regulates neuronal lysosome composition, function, and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network

“…S9 C). Since LAMP1-positive acidic vesicles exhibit a predominantly retrograde movement in axons (Gowrishankar et al, 2021; Lie et al, 2021), we examined the distribution and levels of JIP3/MAPK8IP3, a neuronally enriched scaffolding protein that potentially links axonal endo-lysosomes and motors and regulates their retrograde axonal transport (Gowrishankar et al, 2021; Rafiq et al, 2022). Interestingly, JIP3 protein level is significantly increased in AP-4 i 3 Neurons compared to Control i 3 Neurons (Fig.…”

The axonal endolysosomal and autophagic systems

“…neurons accumulate immature and mostly stationary prelysosomes (see below) containing high levels of the amyloid precursor protein processing enzymes BACE1 and presenilin-2 in axonal swellings (Gowrishankar et al, 2017) with a concomitant increase in Aβ42 production (Gowrishankar et al 2020). Interestingly, a local disruption of microtubules and the axonal actin-spectrin cytoskeleton, phenotypes that are accompanied by an increase in total and phosphorylated tau protein, have been recently found in JIP3 KO iPSC-derived cortical glutamatergic neurons, phenotypes that are further aggravated by the co-depletion of its paralog JIP4 (Rafiq et al 2020). A tight link between the retrograde dynein-driven transport of lysosomes and the cytoskeletal scaffold protein Septin-9 has been reported in non-neuronal cells (Kesisova et al 2020).…”

“…Interestingly, a local disruption of microtubules and the axonal actin‐spectrin cytoskeleton, phenotypes that are accompanied by an increase in total and phosphorylated tau protein, have been recently found in JIP3 KO iPSC‐derived cortical glutamatergic neurons, phenotypes that are further aggravated by the co‐depletion of its paralog JIP4 (Rafiq et al . 2020). A tight link between the retrograde dynein‐driven transport of lysosomes and the cytoskeletal scaffold protein Septin‐9 has been reported in non‐neuronal cells (Kesisova et al .…”