# Novel Pathways to Excitotoxicity in Multiple Sclerosis Caused by Inappropriate Intrusion of an Axonal Mitochondrial Anchor Syntaphilin into Dendrites

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $399,759

## Abstract

The premise of this RO1 is to test a R21-derived hypothesis that inappropriate intrusion of a mitochondrial
anchoring protein, Syntaphilin (SNPH), into neuronal dendrites is harmful in Progressive Multiple Sclerosis
(MS). Progressive MS refers to the late-phase of MS and currently this disease phase has no treatments.
SNPH is normally expressed only in axons. Surprisingly, under support from a R21, we discovered that SNPH
intrudes into dendrites of Purkinje cells in the cerebellum and causes excitotoxicity in a rodent model (Shiverer)
for Progressive MS (Joshi et al., 2019, Cell Reports, Article In Press 15th October). This discovery suggests
that targeting SNPH to block intrusion into dendrites is a novel treatment for Progressive MS. In this follow-up
RO1, we will address three important questions raised by our R21 discovery highly relevant to the basic
science and clinical aspect of MS. In Aim #1, we will test the hypothesis that the pathology of dendritic SNPH
intrusion in the grey matter is de-coupled from the pathology of white matter. We will test this hypothesis by
showing that curing white matter pathology in the Shiverer model (by genetically suppressing axonal
degeneration and by remyelination therapy) will not prevent the pathology of dendritic SNPH intrusion. In Aim
#2, we will test the hypothesis that dendritic SNPH intrusion causes excitotoxicity by biasing the activation of
NMDA receptors towards the pro-death, extra-synaptic NMDA receptors. In Aim #3, we will test the hypothesis
that the glutamate released by synaptic activity, when it spills over to the extra-synaptic region as exacerbated
by dysfunctional glutamate uptake, constitutes an early glutamate signaling cascade that triggers dendritic
SNPH intrusion.
Conclusion – SNPH is a key protein that controls mitochondrial movement with multi-faceted effects on
neuronal behaviors in health and disease. Since the cloning of SNPH in 2000, the studies of SNPH in neurons
have been exclusively in axons. The Novelty of this RO1 is a paradigm shift to pioneer the study of SNPH in
dendrites. The Translational Significance is the surprising discovery that dendritic SNPH mediates
excitotoxicity in Progressive MS, thereby opening up new insights to treat MS in this incurable late-phase.

## Key facts

- **NIH application ID:** 10409730
- **Project number:** 5R01NS118198-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SHING Yan CHIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $399,759
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409730

## Citation

> US National Institutes of Health, RePORTER application 10409730, Novel Pathways to Excitotoxicity in Multiple Sclerosis Caused by Inappropriate Intrusion of an Axonal Mitochondrial Anchor Syntaphilin into Dendrites (5R01NS118198-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10409730. Licensed CC0.

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