# Junctophilin-3, calcium homeostasis, and neuronal dysfunction in HDL2

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2020 · $457,000

## Abstract

Huntington's disease-like-2 (HDL2), discovered and genetically defined by the Margolis group, is an autosomal
dominant neurodegenerative disorder, clinically indistinguishable from Huntington's disease (HD). Like HD, the
neuropathology of HDL2 is characterized by cortical and striatal neurodegeneration and the presence of neuronal
protein aggregates. HDL2 is caused by a CTG/CAG expansion on chromosome 16q24. Normal alleles contain
6-28 triplets, while pathogenic repeats range from 40-59 triplets, again remarkably similar to HD. In the CTG
orientation, the repeat falls in the gene junctophilin-3 (JPH3). A series of pathological, animal model, and cell
model studies by the Margolis lab suggest that HDL2 pathogenesis is multifactorial, involving both gain- and
loss-of-function mechanisms. Here we propose to investigate the pathogenic role of loss of JPH3 protein. JPH3
is one of a conserved family of proteins that, along with JPH4, brings endoplasmic reticulum into close contact
with plasma membrane (PM). In neurons, this contact brings together ER ryanodine receptors, calcium channels,
and potassium channels that as a complex regulate slow after-hyperpolarization current and hence neuronal
function. Based on our findings that JPH3 transcript and protein is reduced in human HDL2 post-mortem brain
samples, and that Jp3 KO mice exhibit motor abnormalities, we hypothesize that the HDL2 pathogenesis stems
at least partially from loss of JPH3 expression, which is sufficient to cause dysfunctional Ca homeostasis and
altered neuronal excitability and function. Our goal here is to test this hypothesis using sensitive calcium imaging
and electrophysiological measures. In Aim 1, we will determine the impact of loss of JP3/JPH3 on calcium
homeostasis and neuronal function, and the electrophysiological parameters that can best detect this,
in primary striatal neurons and coronal sections from Jp3 KO mice, and in human iPS cells differentiated into
mature striatal medium spiny neurons (MSNs) in which JPH3 is reduced. In Aim 2, we will determine the
impact of the HDL2 expansion mutation on Ca homeostasis and neuronal function, and whether this
effect is at least partly the consequence of loss of JPH3, using a series of human HDL2 and control iPSC
lines differentiated into MSNs. The experiments in these aims will help determine the role of JPH3, and more
generally the integrity of the PM-ER junction, in neuronal function and dysfunction, and in the pathogenesis of
neurological disorders. We anticipate that the tools, methods, and data generated through the proposed
experiments will enable us to compete for long-term funding to systematically explore HDL2 pathogenesis, and
the more general role of the ER-PM junction in neurological disorders. Finally, the study is a collaboration
between investigators with complementary expertise at Johns Hopkins and Howard University, and provides the
opportunity for underrepresented students at Howard to gain access to the full re...

## Key facts

- **NIH application ID:** 10103873
- **Project number:** 1R21NS119671-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** RUSSELL L MARGOLIS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $457,000
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10103873

## Citation

> US National Institutes of Health, RePORTER application 10103873, Junctophilin-3, calcium homeostasis, and neuronal dysfunction in HDL2 (1R21NS119671-01). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/10103873. Licensed CC0.

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