# Bioenergetic and Proteolytic Impact of Ubiquitin-like Pathways in Metabolically Stressed Neurons

> **NIH NIH F32** · J. DAVID GLADSTONE INSTITUTES · 2020 · $67,446

## Abstract

PROJECT SUMMARY
The aging process and many aging-associated diseases like Parkinson's disease (PD) are hypothesized to be
caused by a decline in cellular energy and mitochondrial function. Cellular energy is presumably critical to many
cellular processes including protein degradation, a process that is disrupted in neurodegenerative disease.
Identifying genes that modulate levels of ATP, the main energy-carrying molecule in all cells, could then be
critical to slowing or reversing aging-associated pathology, preserving neuron function in response to stress, and
providing insight into how energy failure contributes to disease. However, that analysis has been limited by a
lack of tools to screen the genome at high throughput for modifiers of ATP levels, causing a critical gap in
knowledge of genetic contributors to energy failure. We have developed a unique screening paradigm to address
this knowledge gap by combining genetically encoded ATP sensors with CRISPR-based whole-genome
screening technology within cells exposed to acute metabolic stress. With this approach, we have identified
three poorly-understood gene pathways that have a prominent impact on ATP levels specifically when cells are
metabolically restricted to using only respiration. These pathways are triggered in response to cellular stress,
but have also been observed in the pathophysiology of neurodegenerative diseases. While these pathways all
regulate key facets of protein metabolism and stress response under normal metabolic conditions, it is unclear
how compromised metabolism and low ATP affect these pathways' contributions to the elimination of protein
stresses commonly associated with neurodegenerative diseases. We hypothesize that in metabolically-stressed
neurons, these stress-responsive pathways exacerbate energy failure and protein accumulation. We will
address this hypothesis by investigating if and how these processes affect ATP levels in neurons, as well as the
functional consequences of these pathways on protein degradation and survival of metabolically stressed
neurons. Successful completion of these aims will provide new insight into the relation between energy
homeostasis and proteostasis, as well as the progression of neurodegeneration under metabolic stress.

## Key facts

- **NIH application ID:** 10074126
- **Project number:** 5F32AG063457-02
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** Neal Bennett
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10074126

## Citation

> US National Institutes of Health, RePORTER application 10074126, Bioenergetic and Proteolytic Impact of Ubiquitin-like Pathways in Metabolically Stressed Neurons (5F32AG063457-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10074126. Licensed CC0.

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