# Mitochondrial Fragmentation and Neurodegeneration in Huntington's Disease

> **NIH NIH R01** · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · 2021 · $318,653

## Abstract

The long-term goal of our research is to develop a rational basis for neuroprotective
strategies in order to prevent the onset and to slow the progression of Huntington's disease
(HD). Increasing evidence suggests that mutant huntingtin (mHtt) and structural and functional
abnormalities of mitochondria are involved in neuronal damage and neuronal loss in HD.
Several lines of evidence support the involvement of mitochondrial abnormalities in HD
progression and pathogenesis: 1) Increased expression levels of the mitochondrial fission
genes Drp1 and Fis1 have been found in postmortem tissues from affected brain regions in HD
patients and in striatal and cortical tissues from BACHD transgenic mice; 2) Decreased
expression levels of the mitochondrial fusion genes Mfn1, Mfn2, and Opa1 have been found in
these same affected regions from HD patients and BACHD transgenic mice; 3) Drp1 interacts
with mHtt, and this interaction increases as HD progresses; 4) Increased levels of GTPase Drp1
enzymatic activity have been found in HD neurons; and 5) Decreased mitochondrial mass and
motility, reduced anterograde axonal transport of mitochondria, and reduced synaptic viability
have been found in primary neurons from BACHD transgenic mice. A therapeutic strategy for
HD may involve inhibiting excessive mitochondrial fragmentation. Several mitochondrial fission
inhibitors have been identified, including the mitochondria division inhibitor Mdivi1. Mdivi1 has
been studied using ischemia/reperfusion injury models, renal injury, and oxygen-glucose
deprivation. Findings have revealed that Mdivi1 reduces mitochondrial fission and increases
mitochondrial fusion, and maintains mitochondrial function and cell survival. In studies of
mitochondrial dynamics in an HD-stable striatal cell line that carries 111 polyQ repeats,
researchers found reduced levels of fission genes and increased levels of fusion genes in
HDQ111 cells treated with Mdivi1. Mdivi1-treated HDQ111 cells also showed increased
mitochondrial function and synaptic activity, suggesting that Mdivi1 protects mitochondrial
structure and function, and enhances cell survival. The current application seeks to determine
whether a partial reduction of Drp1 in neurons from BACHD transgenic mice and HD knockin
mice decreases mitochondrial fission and decreases mHtt-induced toxicity; and whether Mdivi1
in neurons from BACHD transgenic mice and HD knockin mice reduces excessive mitochondrial
fragmentation and enhances mitochondrial function and synaptic activity. The outcome of this
research will be an elucidation of genetic and pharmacological strategies that may reduce
excessive mitochondrial fragmentation and increase neuronal survival and synaptic functions in
HD-affected neurons.

## Key facts

- **NIH application ID:** 10232368
- **Project number:** 5R01NS105473-05
- **Recipient organization:** TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
- **Principal Investigator:** P. Hemachandra Reddy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $318,653
- **Award type:** 5
- **Project period:** 2017-09-25 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232368

## Citation

> US National Institutes of Health, RePORTER application 10232368, Mitochondrial Fragmentation and Neurodegeneration in Huntington's Disease (5R01NS105473-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10232368. Licensed CC0.

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