# CRMP2, mitochondria, and Huntington’s disease

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $561,046

## Abstract

Mitochondrial dynamics, manifest as ability of mitochondria to change morphology and motility, play a vital role
in neuronal response to fluctuating energy demands. Impairment of mitochondrial dynamics contributes to
different disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases (HD). In HD, interaction of
mutant huntingtin (mHtt) with dynamin related protein 1 (Drp1) results in an increased Drp1 activity, leading to
augmented mitochondrial fission, accompanied by reduced mitochondrial traffic. Despite significant effort, the
molecular mechanisms, leading to mHtt-induced changes in mitochondrial morphology and motility are not
completely understood. In preliminary experiments, we found that CRMP2, a protein implicated in axon
guidance and regulation of neurite outgrowth, regulates mitochondrial dynamics. A mechanistic link between
CRMP2 and regulation of mitochondrial dynamics has never been investigated. CRMP2 binds to neuronal
mitochondria and in its dephosphorylated form to mHtt. CRMP2 physically interacts with Drp1, Mitofusin 2, and
Miro 2, proteins involved in regulation of mitochondrial fission, fusion, and motility, respectively.
Downregulation of CRMP2 with siRNA leads to increased fission and reduced mitochondrial traffic, implicating
CRMP2 in regulation of mitochondrial dynamics. CRMP2 hyperphosphorylation after inhibition of protein
phosphatases 1 and 2A correlates with augmented fission and reduced mitochondrial traffic. Conversely,
decreasing CRMP2 phosphorylation can prevent these alterations. Finally, we found CRMP2 downregulation
and hyperphosphorylation in striatal tissues from YAC128 HD mouse model and in postmortem striatal tissues
of HD patients. Overall, the literature and our preliminary data strongly suggest that CRMP2 is involved in
regulation of mitochondrial morphology and motility and CRMP2 hyperphosphorylation contributes to
HD pathogenesis leading to excessive fission, reduced mitochondrial traffic, and neuronal loss.
Dephosphorylated CRMP2 binds to mHtt and to proteins involved in mitochondrial dynamics and reduces their
activities, whereas CRMP2 downregulation and hyperphosphorylation disrupts these protein-protein
interactions, liberates binding partners of CRMP2, and increases their activities. In Aim 1, we will determine
CRMP2 localization in mitochondria, establish protein interaction partners, and assess the extent to which
CRMP2 regulates mitochondrial dynamics in neurons. In Aim 2, the mechanisms of CRMP2-medited regulation
of mitochondrial dynamics will be determined. In Aim 3, we will establish CRMP2-mediated mechanisms
contributing to defects of mitochondrial dynamics and cell death in human neurons expressing mHtt. Finally, in
Aim 4, we will assess to what extent CRMP2 dephosphorylation alters protein-protein interactions, protects
neurons, and corrects behavioral deficits in animal models of HD. The proposed study will considerably
improve our understanding of HD pathophysiology, lay a s...

## Key facts

- **NIH application ID:** 9884828
- **Project number:** 5R01NS098772-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Nickolay Brustovetsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $561,046
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884828

## Citation

> US National Institutes of Health, RePORTER application 9884828, CRMP2, mitochondria, and Huntington’s disease (5R01NS098772-04). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9884828. Licensed CC0.

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