# Enhancing Mask/ANKHD1 activity to protect against Tau-induced neurodegeneration

> **NIH NIH R21** · LSU HEALTH SCIENCES CENTER · 2021 · $404,250

## Abstract

Enhancing Mask/ANKHD1 activity to protect against Tau-induced neurodegeneration
Abstract
A common pathophysiological feature of both inherited and sporadic neurodegenerative
diseases such as Alzheimer’s disease is the cytoplasmic accumulation of inclusions containing
aggregate-prone proteins such as Tau. Mounting evidence also suggested that such abnormal
inclusions in neurons and glial cells of neurodegenerative disease patients can spread across
cellular boundaries within the nervous system in a prion-like manner. Therefore, enhancing the
clearance of the toxic protein aggregates holds tremendous therapeutic potential for treating
neurodegeneration. We found that upregulating Mask – a conserved Ankyrin repeats and KH
domain protein (the human homologue is called ANKHD1) – in fly neurological disease model
markedly suppresses human mutant Tau-, FUS- and TDP-43-induced degeneration. We next
obtained biochemical, cellular, and genetic evidence that Mask is both necessary and sufficient
to promote clearance of ubiquitinated proteins, and it does so by promoting lysosomal
acidification and enhancing the flux of autophagy. We also found that the mammalian
homologue of Mask, ANKHD1, may also promote autophagic flux. These results led us to
hypothesize that enhancing Mask/ANKHD1 activity promotes the autophagy/lysosomal
pathway, which has an overall beneficial effect in removing of toxic protein aggregates, and
therefore may have the potential to be further developed and tested as a therapeutic strategy for
Alzheimer’s disease. This grant aims to test 1) whether Mask-mediated promotion of lysosomal
function suppresses neurodegeneration induced by human Tau in flies; and 2) whether
ANKHD1 co-expression suppresses neuron-specific degeneration induced by human mutated
Tau in mouse models.

## Key facts

- **NIH application ID:** 10288299
- **Project number:** 1R21NS123861-01
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** Chunlai Wu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,250
- **Award type:** 1
- **Project period:** 2021-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288299

## Citation

> US National Institutes of Health, RePORTER application 10288299, Enhancing Mask/ANKHD1 activity to protect against Tau-induced neurodegeneration (1R21NS123861-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10288299. Licensed CC0.

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