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A toxic gain-of-function variant in MAPK8IP3 provides insights into JIP3 cellular roles
Wei Zhang1, Swapnil Mittal1, Ria Thomas1
1n-Lorem Foundation, Carlsbad, California, USA.
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.
Insights
A MAPK8IP3 gene mutation causes toxic gain-of-function, disrupting axonal transport and leading to neurodevelopmental disorders. Antisense oligonucleotides effectively reduced mutant JIP3 levels in cells, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The MAPK8IP3 gene encodes JIP3, a protein crucial for axonal transport via the kinesin-1 complex.
- Mutations in MAPK8IP3 are associated with severe neurodevelopmental disorders, including intellectual disability and autism.
Purpose of the Study:
- To investigate the functional consequences of a specific MAPK8IP3 missense mutation (R578C) linked to neurodevelopmental deficits.
- To explore the potential of antisense oligonucleotides as a therapeutic intervention for MAPK8IP3-related disorders.
Main Methods:
- Characterization of the R578C mutation's effect on JIP3 protein function and cellular pathways.
- Assessment of axonal transport, specifically of late endosomes.
- Analysis of c-Jun N-terminal kinase and dopamine receptor signaling pathways.
- In vitro evaluation of phosphorothioate-modified antisense oligonucleotides for JIP3 reduction.
Main Results:
- The R578C mutation results in a toxic gain-of-function, altering JIP3's interactome and disrupting axonal transport.
- The mutation increases c-Jun N-terminal kinase signaling, promoting apoptosis, and affects dopamine receptor 1 signaling.
- Non-allele-selective antisense oligonucleotides significantly reduced both mutant and wild-type JIP3 levels in vitro with good cellular tolerance.
Conclusions:
- The study reveals novel roles for JIP3 in cellular processes and disease pathogenesis.
- Targeting JIP3 reduction with antisense oligonucleotides presents a promising therapeutic avenue for neurodevelopmental disorders caused by MAPK8IP3 mutations.
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