# Phosphoinositide signaling: novel potential targets for Huntington disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $449,225

## Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG
trinucleotide repeat expansion in exon 1 of the Huntingtin (HTT) gene. There are no effective treatments for
this fatal disease. Thus, identification of new target pathways to mitigate Huntington's disease is critical. We
discovered two targets that lower mutant HTT protein (mHTT) and thus hold potential for disease-modifying
therapy. In an unbiased, high-throughput screen, we discovered PIP4Kγ-INH, an allosteric inhibitor of PIP4Kγ.
Treatment of HdhQ111 knock-in mouse striatal neurons with PIP4Kγ-INH, reduced the levels of HTTQ111.
Moreover, exposure of Huntington patient fibroblasts to inhibition or knock-down of PIP4Kγ, reduced mutant
huntingtin protein. PIP4Kγ converts PI5P to PI(4,5)P2. We determined which phosphoinositide lipids are
impacted by PIP4Kγ-INH, and identified an orthogonal approach to induce similar changes in these lipids.
Notably this new approach might also lower mutant HTT aggregates. Indeed, co-expression of huntingtin
exon1-polyQ74-GFP (httQ74-GFP) combined with activation of a lipid kinase reduced httQ74 aggregates by
>35%. Thus, orthogonal approaches that change phosphoinositide lipids have the potential to lower HD levels.
The overall goal of this proposal is to determine whether inhibition of PIP4Kγ and/or activation of a lipid kinase
should be test for the potential to ameliorate phenotypes associated with HD. This goal will be pursued with the
following aims: 1) Determine the effects of activation of a specific lipid kinase on cellular levels of mutant HTT.
2) Determine mechanisms whereby inhibition of PIP4Kγ or activation of a specific lipid kinase lowers mutant
HTT. 3) Determine whether inhibition of PIP4Kγ and/or activation of a specific lipid kinase mitigates disease
pathogenesis in animal models of HD. We predict that the outcomes of these studies will reveal that one or
both lipid kinase targets are attractive options for further testing as possible disease-modifying agents in
preclinical studies.

## Key facts

- **NIH application ID:** 9948034
- **Project number:** 5R01NS099340-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Lois S Weisman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $449,225
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948034

## Citation

> US National Institutes of Health, RePORTER application 9948034, Phosphoinositide signaling: novel potential targets for Huntington disease (5R01NS099340-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9948034. Licensed CC0.

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