# Deletion of Mitochondrial Anchoring Protects Late Phase Multiple Sclerosis

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $334,688

## Abstract

PROJECT SUMMARY
 Human MS is a biphasic demyelinating disease: there is an initial relapsing-remitting phase (RRMS)
followed by a secondary progressive phase (SPMS). The SPMS is currently incurable. To examine the
pathology of SPMS, we studied a monophasic mouse model (Shiverer) that exhibits only the progressive
phase. Under support of an R-21 (precursor to this RO1), we made the surprising discovery that deleting
SNPH (a major mitochondrial anchoring protein) in Shiverer produces dramatic neuroprotection. In contrast,
deleting SNPH offers no protection in another monophasic animal model (EAE/B6) that exhibits only the RRMS
phase. We hypothesize that SNPH has a biphasic role in human MS (it is beneficial in RRMS and harmful in
SPMS) and that inhibiting SNPH in SPMS is a novel therapy for progressive MS. This grant extends the R-21
results in mechanistic (Aim 1) and translational (Aim 2 & 3) directions.
In Mechanistic Aim 1, we will examine how SNPH-KO protects pathologic neurons in vitrro by a two-
pronged action to activate neuroprotective mitophagy and mitochondrial fusion pathways. In Translational Aim
2, we will characterize SNPH pathology in a novel biphasic mouse model (EAE/NOD) that is superior to our
monophasic models in expressing both RRMS and SPMS phases to better mimic human biphasic MS. The
climax of this grant is Translational Aim 3. We will design a treatment for the SPMS phase in the biphasic
mouse model as a possible future treatment for human progressive MS. Our treatment design is two-fold. First
is timing of therapy. We will use conditional SNPH-KO strategy to show that the best timing for treatment is at
the transition from RRMS to SPMS when SNPH stops being beneficial and starts becoming harmful. Second is
combinatorial therapy. We will examine whether a combinatorial therapy (SNPH-KO and anti-inflammation)
might completely eradicate neurodegeneration in the progressive phase of the biphasic mouse model.
Conclusion: This project formulates a brand new framework for designing treatments for the currently
incurable progressive MS. Through a biphasic SNPH hypothesis, we pinpoint a key mitochondrial anchoring
protein whose function switches from being beneficial to harmful during MS progression. The crux of this grant
is to validate a biphasic mouse model to mimic biphasic human MS, then treat the mouse by targeting SNPH in
the late phase using conditional and combinatorial strategies as a future step to treat human progressive MS.

## Key facts

- **NIH application ID:** 9873102
- **Project number:** 5R01NS100924-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SHING Yan CHIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $334,688
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873102

## Citation

> US National Institutes of Health, RePORTER application 9873102, Deletion of Mitochondrial Anchoring Protects Late Phase Multiple Sclerosis (5R01NS100924-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873102. Licensed CC0.

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