# Convergence of tauopathy and Huntington's disease through selective autophagy

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $558,425

## Abstract

Abnormal accumulation of misfolded Tau protein is tightly linked pathogenically to a group of brain degenerative
disorders including Alzheimer's disease (AD) that are collectively called Tauopathies. Currently there is no
effective prevention or treatment avenue against these debilitating diseases. Targeted clearance of misfolded,
pathogenic Tau species thus represents one potentially vital therapeutic strategy. A flurry of recent studies,
corroborating with a long history of clinical observations, have led to the proposal that Huntington's disease (HD),
another fatal neurodegenerative disorder caused by an abnormal expansion of a glutamine tract (polyQ) in
Huntingtin (HTT) protein, is also a tauopathy disease. Interestingly, while working on the HTT homolog in
Drosophila, we found that normal HTT can promote the clearance of certain misfolding-prone Tau species by
acting as a scaffold in selective autophagy, a subtype of autophagy-lysosomal pathway that requires cargo
receptors such as p62/SQSTM1 to recognize and target specific cytosolic components for lysosomal degradation.
Subsequent studies in mammalian cells and in mouse AD models further supported this finding, which, together
with the known autophagic phenotypes in HD cells and in mice expressing polyQ-deleted HTT, suggest a scenario
that polyQ expansion in HTT disrupts its own activity in promoting selective autophagy and normal Tau turnover,
leading to the Tau pathology. Such a hypothesis not only supports the HTT-mediated autophagy pathway as a
converging mechanism linking HD and Tauopathy, but also raises the promise of harnessing this conserved innate
protective pathway for targeted removal of pathogenic Tau in Tauopathies. In this joint R01 application, we will
use our established assays in the complementary Drosophila, cellular, and mouse model systems to rigorously
and systematically test this hypothesis at the genetic, biochemical and functional levels. Taking advantage of the
conserved HTT and autophagy pathways, as well as the availability of a plethora of Tau models and Tau toxicity
assays established in Drosophila, we will use flies as an in vivo tool to evaluate the effect of polyQ lengths on the
autophagic function of HTT, and to examine the discrete Tau species to search for the ones that can be degraded
by the HTT-mediated selective autophagy and for their common signatures; Using mammalian cell-based assays,
we will validate the findings from the flies and also probe the molecular mechanisms underlying the modulatory
role of the polyQ stretch on HTT activities. Finally, by manipulating Tau and HTT in the well-characterized mouse
HD and AD models, we will directly validate our hypothesis and findings in an in vivo setting that is physiologically
closer to humans. Completion of this project will reveal novel mechanistic insight into the crosstalk between
Tauopathy and HD, and establish the feasibility of future pharmacological exploitation of the novel selectively
autophag...

## Key facts

- **NIH application ID:** 10173589
- **Project number:** 5R01AG057509-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Sheng Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $558,425
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173589

## Citation

> US National Institutes of Health, RePORTER application 10173589, Convergence of tauopathy and Huntington's disease through selective autophagy (5R01AG057509-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10173589. Licensed CC0.

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