# Neuronal function of huntingtin-associated protein

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $396,395

## Abstract

Project Summary
Neuronal function of huntingtin-associated protein
 Huntingtin-associated protein-1 (Hap1) was first identified as a neuronal protein that interacts with the
Huntington's disease (HD) protein, huntingtin (Htt). Hap1's binding to Htt is enhanced by expanded
polyglutamine repeats in the N-terminal region of Htt. Moreover, unlike Htt, which is ubiquitously expressed,
Hap1 is expressed primarily in neuronal cells, suggesting that it is a good candidate for involvement in the
selective neurodegeneration in HD. Extensive studies have shown that Hap1 and Htt associate with each other
in the intracellular trafficking of various vesicles and proteins. Also, like Htt, Hap1 is essential for early
development and neurogenesis. Our recent studies showed that the function of both Hap1 and Htt is cell type
and age dependent. We also know that neurogenesis is important for early brain development and the repair of
neuronal damage in the adult brain. Although both Htt and Hap1 participate in neurogenesis, and impaired
neurogenesis is seen in HD brains, whether Hap1 and Htt work together to regulate neurogenesis and whether
mutant Htt affects neurogenesis via its interaction with Hap1 remain unknown.
 We hypothesize that Hap1 and Htt participate in age- and environmental stress-dependent neurogenesis
and that mutant Htt affects this function by its interaction with Hap1. To test this hypothesis, we will use Hap1
KO and Htt KO mice as well as HD140Q knock-in mice to examine the role of the interaction of Hap1 and Htt in
postnatal and adult neurogenesis. We will focus on neurogenesis in the hypothalamus and hippocampus, as
loss of Hap1 in these two regions is found to cause body weight loss and depression, two well-known
phenotypes that also occur in HD patients. We will use CRISPR/Cas9 to selectively deplete Htt expression or
to increase the production of N-terminal mutant Htt in HD140Q KI mice to examine whether they have any
effects on neurogenesis. Using these approaches, we propose two aims in this application. Aim 1 will
investigate whether Hap1 and Htt work together to promote neurogenesis. Aim 2 will explore whether mutant
Htt affects neurogenesis via its abnormal interaction with Hap1. The studies seek to provide new insight into
the cell type- and age-dependent function of Hap1 and Htt, as well as the selective neuropathology of HD.
Findings from these studies will also help us uncover therapeutic strategies for the specific neuropathology and
phenotypes in HD.
!

## Key facts

- **NIH application ID:** 9979960
- **Project number:** 5R01NS036232-21
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Andrew P Escayg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,395
- **Award type:** 5
- **Project period:** 1998-01-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979960

## Citation

> US National Institutes of Health, RePORTER application 9979960, Neuronal function of huntingtin-associated protein (5R01NS036232-21). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979960. Licensed CC0.

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