# Modulation of neuronal atrophy in Huntington's disease

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $275,625

## Abstract

Project Summary/Abstract
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disease caused by a CAG triplet
expansion mutation coding for glutamine in exon 1 of the Huntingtin (HTT) gene. Mutant HTT (mHTT) protein
disrupts a number of molecular and cellular processes. The Ras-related Rho GTPases are molecular switches
that regulate a number of processes, including cell proliferation, differentiation, migration, transcription, and
actin dynamics. Long-term RhoA inactivation mediated by p190RhoGAP and a Rap-dependent RhoGAP
(ARAP3) is essential for neurite outgrowth. In our preliminary studies using in vitro HD striatal cell lines and HD
transgenic mice, we discovered striking abnormalities of the ARAP3-RhoA pathway that we found in human
HD postmortem brain. Rho-GTPase activity was increased 24-fold in the striatal lysates of HD patients while
ARAP3 (ArfGAP with RhoGAP Domain, ankyrin repeat and PH Domain 3), a negative regulator of RhoA, was
significantly down regulated. ARAP3 overexpression in striatal cells restored neuronal size and function that
were affected by a constitutively active mutant RhoA. Delivery of AAV-shRNA ARAP3 significantly exacerbated
neuronal atrophy in the striatum of YAC128 mice. Based on these findings we propose a novel hypothesis
that altered ARAP3 function and RhoA activity cause potentially reversible F-actin stress fiber
formation and cytoskeletal disruption which in turn lead to neuronal atrophy and dysfunction in HD. To
investigate whether impaired ARAP3-RhoA pathway underlies the cellular and molecular basis of neuronal
atrophy that is reversible, we propose three specific aims: Aim 1: To investigate alteration of ARAP3 and
RhoA levels in postmortem brains, transgenic animal models, and cell line models of HD. We will
determine the spatiotemporal change of ARAP3, RhoA, and cytoskeleton structures in the striatum by using
Western blot, qPCR, and confocal microscopy combined with 3-D reconstruction image analysis. Aim 2: To
determine the relationship between ARAP3 and the RhoA pathway, and identify molecular and cellular
mechanisms of neuronal atrophy in HD. We will use time-resolved fluorescence resonance energy transfer
(FRET)-based RhoA biosensor and live cell imaging to identify how loss or gain of ARAP3 function affects the
RhoA activity in HD striatal cells. Aim 3: To examine the in vivo effects of ARAP3 and RhoA on neuronal
atrophy and function, motor activity, and survival in HD mouse models. We will perform cross sectional
studies to determine the loss of ARAP3 function and the gain of RhoA function on motor symptoms and
survival rates in HD mice. We will analyze F-actin stress fiber formation and DARPP32 activity in the striatal
neurons of mice. We will further measure neuropathological changes such as neuronal size/number and mHTT
aggregation. Our studies will identify novel molecular and cellular mechanisms of neuronal atrophy in the
pathogenesis of HD and provide a therapeutic approach...

## Key facts

- **NIH application ID:** 10248302
- **Project number:** 5R01NS109537-04
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Junghee Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $275,625
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248302

## Citation

> US National Institutes of Health, RePORTER application 10248302, Modulation of neuronal atrophy in Huntington's disease (5R01NS109537-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10248302. Licensed CC0.

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