# The role of HspB8 (Hsp22) in maintaining tau proteostasis

> **NIH NIH F31** · UNIVERSITY OF ROCHESTER · 2020 · $45,520

## Abstract

Age is the primary risk factor for numerous neurodegenerative diseases, with Alzheimer’s disease (AD) being
the most prevalent. During aging there is a decline in protein quality control systems which likely contributes to
the formation of the molecular hallmarks of AD; with the accumulation of pathological tau species being a key
feature of the disease. Dysfunction of autophagy and mechanisms that promote protein solubility occur early in
the pathogenesis of AD. Impairment of these pathways likely contributes to the accumulation and mislocalization
of tau, which plays a fundamental role in the pathogenesis of AD. Recent data provide compelling evidence that
the stress responsive, small heat shock protein B8 (HspB8) plays a key role in maintaining proteostasis;
decreased levels result in increases in insoluble proteins and decreases in autophagy. In addition, a recent study
revealed that HspB8 and the multidomain Bcl2 associated athanogene 3 (BAG3) are expressed at higher levels
in inhibitory neurons which are more resistant to tau pathology. These findings are very intriguing given that
HspB8 is a key binding partner of BAG3, and thus they may work together to promote tau proteostasis. Further,
our preliminary data suggest that HspB8 likely plays a key role in maintaining tau solubility and promoting
autophagy. The UNDERLYING PREMISE of this proposal is that in neurons HspB8 plays a critical role in
mediating tau solubility and autophagy, and thus the turnover of tau. The importance of HspB8 in mediating
neuronal proteostasis is illustrated by the fact that previous findings indicate that HspB8 facilitates the autophagic
clearance of disease relevant, aggregate prone proteins such as truncated TDP-43 species. Nonetheless, our
understanding of how HspB8 regulates tau clearance and solubility is very limited. CRITICAL KNOWLEDGE
GAPS include: how HspB8 levels affect tau solubility and accumulation, the role of HspB8 in modulating
autophagic flux/ autophagosome-lysosome fusion, and if the expression level of HspB8 in neuronal populations
correlates with their relative susceptibility to tau pathology. Considering these critical knowledge gaps the
OVERALL HYPOTHESIS of this proposal is that HspB8 plays a role in maintaining tau solubility and facilitating
autophagic flux, and thus tau clearance. In the context of this overall hypothesis the specific aims of this proposal
are: (1) To test the hypothesis that HspB8 mediates tau solubility and autophagic flux and thus contributes to tau
clearance in a BAG3 dependent manner, (2) To test the hypothesis that HspB8 is differentially expressed in
inhibitory and excitatory neurons which plays a role in determining susceptibility to tau pathology, and (3) To test
the hypothesis that HspB8 protects neurons from tau pathology in vivo. The majority of these studies will be
carried out using primary neuron cultures and mouse models. All in vivo studies will be carried out in older male
and female mice since age lik...

## Key facts

- **NIH application ID:** 10066167
- **Project number:** 1F31AG069369-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Jarreau Harrison
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066167

## Citation

> US National Institutes of Health, RePORTER application 10066167, The role of HspB8 (Hsp22) in maintaining tau proteostasis (1F31AG069369-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10066167. Licensed CC0.

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