# A toxic gain-of-function variant in MAPK8IP3 provides insights into JIP3 cellular roles

## TL;DR

A harmful mutation in the MAPK8IP3 gene causes severe neurological issues by altering protein function, and antisense oligonucleotides can reduce these effects.

## Contribution

The study identifies a toxic gain-of-function mutation in JIP3 and demonstrates therapeutic potential using antisense oligonucleotides.

## Key findings

- The R578C mutation in MAPK8IP3 disrupts axonal transport and increases apoptosis via c-Jun N-terminal kinase signaling.
- Antisense oligonucleotides reduce mutant and wild-type JIP3 levels without causing toxicity in cells.
- The mutation affects dopamine receptor 1 signaling but not dopamine receptor 2 signaling.

## Abstract

Mitogen-activated protein kinase 8 interacting protein 3 (MAPK8IP3) gene encoding a protein called JIP3 is an adaption protein of the kinesin-1 complex known to play a role in axonal transport of cargo. Mutations in the gene have been linked to severe neurodevelopmental disorders, resulting in developmental delay, intellectual disability, ataxia, tremor, autism, seizures, and visual impairment. A patient who has a missense mutation in the MAPK8IP3 gene (c. 1714 C>T, Arg578Cys) (R578C) manifests dystonia, gross motor delay, and developmental delay. Here, we showed that the mutation was a toxic gain-of-function mutation that altered the interactome of JIP3; disrupted axonal transport of late endosomes; increased signaling via c-Jun N-terminal kinase, resulting in apoptosis; and disrupted dopamine receptor 1 signaling while not affecting dopamine receptor 2 signaling. Furthermore, in the presence of the mutant protein, we showed that an 80% reduction of mutant JIP3 and a 60% reduction of WT JIP3 by non-allele-selective phosphorothioate-modified antisense oligonucleotides was well tolerated by several types of cells in vitro. Our study identifies what we believe to be several important new roles for JIP3 and provides important insights for therapeutic approaches, including antisense oligonucleotide reduction of JIP3.

JIP3 mutation R587C acts as a severe toxic gain of function and antisense oligonucleotides (ASOs) correct all proximal pathological phenotypes.