# Nuclear sphingosine kinase 2 in Huntington disease

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $383,428

## Abstract

Huntington’s disease (HD) is one of nine incurable neurodegenerative disorders caused by pathogenic
polyglutamine (polyQ) expansions. Although each polyQ neurodegenerative disease develops via distinct
genetic, molecular and cellular mechanisms, a feature common to all of them is transcriptional dysregulation.
PolyQ-expanded proteins interact abnormally with transcriptional factors and disrupt transcription leading to
neurotoxicity. Thus, normalizing transcription is a therapeutic strategy for HD and for polyQ disorders in
general. A novel neuronal nuclear pathway, the sphingosine kinase 2 (SK2) pathway, regulates transcription by
modulating transcription factors. In our recent paper, we demonstrated that overexpressed SK2 is toxic to
neurons. We discovered that SK2 is hyperphosphorylated in brain samples from a mouse model of HD, the
BACHD mice, indicating its increased activity. In our preliminary data, we also discovered a potential new
binding partner of SK2 − ZHX2, zinc fingers and homeoboxes 2 transcriptional repressor. The ectopic
expression of ZHX2 in primary neurons is also toxic. Remarkably, ZHX2 levels are increased in brain samples
from the BACHD mice. We hypothesize that SK2/ZHX2 is a component of the pathogenic mechanisms in HD
and that inhibiting SK2/ZHX2 signaling will promote survival of HD neurons. In the first aim, we will
characterize the SK2/ZHX2 pathway in primary neurons. In the second aim, we will define the role of
SK2/ZHX2 in HD. We recently demonstrated that an inhibitor of SK2 improves neuronal survival in two rodent
neuron models of HD. Therefore, in the third aim, we will determine if inhibiting or downregulating SK2
alleviates disease phenotypes in HD mice. These studies could form the basis for SK2/ZHX2 pathway–based
drug discovery, with applications to the polyQ disorders.

## Key facts

- **NIH application ID:** 9942905
- **Project number:** 1R01NS115886-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Andrey Tsvetkov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,428
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942905

## Citation

> US National Institutes of Health, RePORTER application 9942905, Nuclear sphingosine kinase 2 in Huntington disease (1R01NS115886-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9942905. Licensed CC0.

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