# Understanding the Relationship Between Protein Homeostasis and Sleep Dysfunction in Mouse Models of Huntington's Disease

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $452,375

## Abstract

Project Summary/Abstract
Sleep dysfunction is a common feature in neurodegenerative diseases, whereas epidemiologic studies
strongly suggest that sleep disruption and chronic short sleep may also be risk factors for the onset of disease.
These observations suggest a bidirectional relationship between neurodegenerative events and sleep
dysregulation, however there is little understanding about the mechanisms that tie them together. Given the
difficulty with modeling sporadic disorders, studying the phenomenon in a defined model system may shed new
insight into this understudied area. Huntington’s disease (HD), which is a hereditary, fully penetrant, progressive
neurodegenerative disorder, shares features that are common to more prevalent neurodegenerative diseases,
such as abnormal protein accumulation, early cognitive changes, and cell type specific degeneration. Although
known for the triad of symptoms characterized by movement, cognitive and psychiatric symptoms, a lesser
known feature of HD is an early onset of circadian rhythm and sleep disturbances. It has been reported that up
to 88% of patients acknowledge having sleep problems, which were rated by 62% as either “very” or “moderately”
important factors contributing towards the patient well-being. Moreover, mouse models of HD capture both
circadian rhythm and sleep disturbances. Together, these data suggest that the neural circuitry regulating sleep
is especially vulnerable to the genetic changes associated with HD. Given the well appreciated role of mutant
Huntingtin (Htt) in the disruption of protein homeostasis, we hypothesize that perturbations in protein
homeostasis disrupts the neural circuitry underlying sleep, and that prolonged sleep dysfunction also reciprocally
disrupts protein homeostasis.
 The autophagy adaptor protein Alfy is required for the turnover of aggregated mutant Htt. We present
preliminary data demonstrating that increased levels of Alfy delays the accumulation of aggregated protein in
the striatum, and delays the onset of motoric dysfunction in two mouse models of HD. Similarly, we show that
sleep disturbances observed in HD mice may also be diminished due to Alfy over-expression. In Aim1, we will
perform correlative analyses between Alfy expression, neuropathological outcomes and sleep behavior to test
the hypothesis that increasing Alfy levels delays the appearance of aggregated mutant Htt in sleep-related brain
regions, which in turn will delay the onset of sleep disturbances. In Aim 2, we will apply chronic sleep deprivation
in presymptomatic HD mice to test the hypothesis that sleep dysfunction may decrease protein homeostasis and
accelerate disease progression via the autophagy pathway. We will determine how sleep deprivation impacts
mutant Htt accumulation and motor dysfunction. Then, we will overexpress Alfy in HD mice and test if it can
delay SD-induced behavioral and neuropathological changes. Finally, we will perform RNA-seq in affected brain
regions to a...

## Key facts

- **NIH application ID:** 10593596
- **Project number:** 1R21NS126979-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Yueqing Peng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $452,375
- **Award type:** 1
- **Project period:** 2022-09-27 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593596

## Citation

> US National Institutes of Health, RePORTER application 10593596, Understanding the Relationship Between Protein Homeostasis and Sleep Dysfunction in Mouse Models of Huntington's Disease (1R21NS126979-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10593596. Licensed CC0.

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