# Determining selective autophagy kinase in modulating neurotoxicity in Huntington's disease model

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $467,945

## Abstract

Our goal is to elucidate molecular mechanism for neuroprotective autophagy in Huntington's disease (HD) and
determine therapeutic potential for selective autophagy in treating the disease. HD is caused by an aberrant
expansion of CAG repeat (polyQ) in the HTT gene, which leads to a toxic gain-of-function in the mutant
huntingtin (mHTT) protein. Despite over 20 years' research, disease-modifying therapeutics is unavailable.
Thus, elucidation of the disease mechanism and mHTT clearance pathways is pivotal for the success of
therapeutic development. Autophagy is a catabolic cellular pathway that clears protein aggregates and injured
organelles through lysosomes as a quality control system. PolyQ-expanded protein aggregates including
fragments of HTT can be degraded by selective autophagy, and thus selective autophagy is considered a drug
target for HD. However, autophagy is a complex process subjected to tight regulation, and how exactly
autophagy selectively degrade mHTT remains poorly understood. We previously showed that ULK1 regulates
p62-mediated selective autophagy under proteotoxic stress. In the context of mHTT, however, we reported
dysregulation of ULK1 kinase activity that connects to reduced VPS34 activity and aberrant p62-selective
autophagy in the brains of HD model zQ175. Our current study suggests that ULK1 deficiency accelerates
mHTT-mediated toxicity. The data thus provides strong evidence for the role of ULK1-p62 mediated selective
autophagy in regulating mHTT toxicity. We hypothesize that ULK1 and p62 are promising modifiers of HD
disease progression. We propose (1) to determine the role and mechanism for ULK1-p62 signaling in the
degradation of mHTT through selective autophagy; (2) to investigate pathogenic mechanism that mHTT
disrupts ULK1 kinase activity and causes ULK1 deficiency-mediated selective autophagy impairment and
neurotoxicity; (3) determine ULK1 kinase activity as a therapeutic target to inhibit mHtt-mediated neurotoxicity
using animal models through genetic and pharmacological approaches. Our study is expected to reveal
molecular mechanism for ULK1 protective function against HD and validate ULK1 kinase activity as a drug
target for the clearance of mHTT and offering neuroprotection.

## Key facts

- **NIH application ID:** 10438575
- **Project number:** 5R01NS117590-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Zhenyu Yue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $467,945
- **Award type:** 5
- **Project period:** 2020-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438575

## Citation

> US National Institutes of Health, RePORTER application 10438575, Determining selective autophagy kinase in modulating neurotoxicity in Huntington's disease model (5R01NS117590-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10438575. Licensed CC0.

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