# Nrf1-dependent Proteotoxic Stress Response

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $181,126

## Abstract

ABSTRACT
 Alzheimer's disease (AD) is the most common cause of age-related dementia
characterized by memory loss and cognitive decline. One of the pathological hallmarks
of AD at the molecular level is the presence of neurofibrillary tangles composed of
aggregates of hyperphosphorylated tau in the neurons leading to severe proteotoxic
stress in these cells. Sustained proteotoxic stress typically results in neuronal cell death
culminating in brain atrophy, a prominent pathological feature of AD. Given that tau can
be degraded by the proteasome as well as the autophagy-lysosomal network, possible
defects in one or both of these catabolic pathways could explain its accumulation in the
diseased neurons. Consistent with this notion, accumulating evidence points to a
progressive decline in the function of both the proteasome and the autophagy-lysosomal
network during the aging process. Therefore, it is important to understand how these
protein clearance systems operate in cells of neuronal origin and elucidate how these
cells handle proteotoxic stress. Our previous studies have established the transcription
factor Nrf1as a key player in responding to cellular proteotoxic stress. Nrf1, by its ability
to induce de novo synthesis of proteasome subunit genes in response to proteasome
inhibitors, promotes the recovery of proteasome activity, thus mitigating proteotoxic
stress and enhancing cellular survival. Interestingly, our preliminary data indicate that
under similar circumstances, Nrf1 can also transcriptionally upregulate multiple
components of the autophagy pathway, and thus could offer the cells an additional route
to cope with proteotoxic stress. Here we propose to investigate this phenomenon further
in cells of neuronal origin that are relevant to AD. If successful, our studies could
cement the role of Nrf1 as a master transcription factor that controls the two major arms
of the cellular protein quality control pathways – the ubiquitin-proteasome system, and
autophagy in neuronal cells. This could lead to future studies aimed at the development
of novel strategies to enhance these protein degradation pathways to mediate tau
clearance and alleviate proteotoxic stress in the AD neurons.

## Key facts

- **NIH application ID:** 10121370
- **Project number:** 3R01GM132396-02S1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Senthil Kumar Radhakrishnan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $181,126
- **Award type:** 3
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121370

## Citation

> US National Institutes of Health, RePORTER application 10121370, Nrf1-dependent Proteotoxic Stress Response (3R01GM132396-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10121370. Licensed CC0.

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