# Mitochondrial dynamics for the maintenance of neuromuscular junctions during aging and in ALS

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $410,577

## Abstract

PROJECT SUMMARY
Mitochondrial dysfunction and neuromuscular junction (NMJ) decline are both prominent features in
amyotrophic lateral sclerosis (ALS), and implicated in the onset and progression of ALS. However, whether
and how mitochondrial dysfunction plays a role in NMJ decline in ALS is not clear. Constant mitochondrial
fission and fusion dynamics are essential for both mitochondrial morphology and function. We and others
recently demonstrated that the impaired mitochondrial fission and fusion dynamics was likely an important
mechanism leading to mitochondrial dysfunction and neurodegeneration in ALS and other various major
neurodegenerative diseases. Interestingly, in our preliminary studies, we found that mitochondria became
highly fragmented in spinal cord motor neurons of ALS patients and the widely studied transgenic SOD1 G93A
mouse model of ALS (SOD1G93A mice). Mitofusin 2 (Mfn2), the key regulator of mitochondrial fusion, was
further found to be reduced in spinal cords of ALS patients and SOD1G93A mice. Excitingly, our newly identified
Mfn2 degradation pathway via calpain was found activated in SOD1G93A mice. Mfn2 deficiency in motor
neurons caused mitochondrial fragmentation, NMJ denervation and neuronal death, whereas forced
expression of Mfn2 in neurons was sufficient to completely abolish mitochondrial fragmentation, NMJ decline
and related skeletal muscle atrophy in SOD1G93A mice even at the endstage. These exciting and promising
preliminary studies suggest that a detailed investigation into the potential role of Mfn2 in the maintenance of
NMJs and related skeletal muscles in ALS is warranted. The following specific aims will be pursued: 1) To
perform detailed assessments of motor function, skeletal muscles, motor neurons and NMJs in Mfn2/SOD1G93A
mice; 2) To elucidate the molecular mechanism underlying Mfn2 reduction in SOD1G93A mice and validate
calpain-mediated Mfn2 degradation as a therapeutic target; 3) To explore the pathways by which neuronal
Mfn2 protects NMJs in Mfn2/SOD1G93A mice. This will be first systematic and mechanistic in vivo study using
novel mouse models, a promising novel synthetic therapeutic peptide and cross-disciplinary approaches to
investigate the role of mitochondrial dynamics in the maintenance of NMJs and function of motor neuron and
muscle in ALS. Our proposed studies of the impact of mitochondrial dynamics on NMJs as a functional unit of
nerve and muscle in the context of ALS will has both scientific (new insight into mechanisms underlying
mitochondrial dysfunction and NMJ decline in ALS) and translational (provide novel therapeutic approaches to
delay or reverse NMJ decline and associated skeletal muscle atrophy in ALS) significance.

## Key facts

- **NIH application ID:** 9842575
- **Project number:** 5R01NS097679-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Xinglong Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $410,577
- **Award type:** 5
- **Project period:** 2017-02-01 → 2020-10-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842575

## Citation

> US National Institutes of Health, RePORTER application 9842575, Mitochondrial dynamics for the maintenance of neuromuscular junctions during aging and in ALS (5R01NS097679-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9842575. Licensed CC0.

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