# Comparison of HD and HDL2 mouse models to reveal common mechanisms of pathogenesis

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2021 · $450,313

## Abstract

Project Summary
 HD is an autosomal dominant neurodegenerative disease, characterized by movement, cognitive and
emotional disorders, with relentless progression to death. There is currently no disease-modifying
treatment for HD. Though clinical suppression strategies are in clinical trials or preclinical development, the
efficacy and tolerability of these treatments remains unknown, hence there is great need to search, in
parallel, for other therapeutic targets. To facilitate prioritizing HD pathways for therapeutic interventions,
we have launched an effort to compare HD with Huntington’s disease-like 2 (HDL2). HDL2, discovered
and genetically defined by our group, is an adult onset autosomal dominant neurodegenerative disorder
that is clinically, genetically, and neuropathologically remarkably similar to HD. Experts cannot distinguish
between the two disorders without genetic testing. Both disorders are caused by a repeat expansion
mutation; the mutation in HDL2 is caused by a CTG/CAG expansion on chromosome 16q24 in the gene
junctophilin-3. Like HD, expanded tracks of polyglutamine probably are the key factor in HDL2
pathogenesis. However, also like HD, RNA transcripts containing the expanded repeat and a loss-of-
function the gene in which the repeat is found likely also contribute to pathogenesis.
 We hypothesize that HD and HDL2 share pathogenic pathways, and that detecting these pathways will
lead to further understanding of both disorders and the development of new therapeutic targets. As part
of our efforts to test this hypothesis, we propose to use CRISPR/Cas9 and ssDNA donors to generate an
HDL2 knock-in (KI) mouse model with either 14 (normal) or ~100 triplets (mutation). We will compare these
new mouse lines with the similar KI HD lines Hdh10/+ and HDh111/+. In Aim 1, we will test the hypothesis
that the HDL2 and HD expansion mutations results in a similar phenotype by comparing the behavior and
neuropathology of HDL2 and HD KI lines. In Aim 2, we will test the hypothesis that similar molecular
mechanisms are associated with HD and HDL2 pathogenesis by using RNAseq to compare the pattern of
gene expression in the HDL2 and HD model mice. If successful, this project will provide the basis for
detailed studies designed to find new therapeutic targets for both HD and HDL2.

## Key facts

- **NIH application ID:** 10347570
- **Project number:** 1R21NS124936-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** RUSSELL L MARGOLIS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,313
- **Award type:** 1
- **Project period:** 2021-09-15 → 2024-03-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347570

## Citation

> US National Institutes of Health, RePORTER application 10347570, Comparison of HD and HDL2 mouse models to reveal common mechanisms of pathogenesis (1R21NS124936-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10347570. Licensed CC0.

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