# Slowing Proteotoxic Neurodegeneration by Boosting Mitochondrial Bioenergetics and Recruiting a Novel Class of Chaperones

> **NIH VA I01** · MIAMI VA HEALTH CARE SYSTEM · 2020 · —

## Abstract

One of the major challenges for the U.S. Department of Veterans Affairs is to extend the health-span
of the veterans and their families as their physical and/or cognitive performance capabilities decline
with age. Human neurodegenerative protein misfolding disorders or proteinopathies, are associated
with abnormal protein depositions in brain neurons. They include polyglutamine (polyQ) disorders
such as Huntington's disease and α-synucleinopathies such as Parkinson's disease. Disclosing the basic
molecular and metabolic alterations that occur during aging of post-mitotic cells such as neurons,
under proteotoxic stress is crucial for understanding the etiology of neuro-proteinopathies.
 Metabolic and mitochondrial alterations are hallmarks of aging and neurodegeneration. Over
the last decade, we and others have shown that enhancement of mitogenesis or overexpression of
NMNAT/NMA1, an enzyme in the NAD+ biosynthetic salvage pathway, act as powerful suppressors of
proteotoxicities in yeast, fly and mouse models. Although the mechanisms involved remain to be fully
understood, our preliminary data suggest that the two mechanisms are independent and that
NMNAT could act as a chaperone to promote clearance of misfolded proteins. Recent screens in
yeast models in our lab allowed us to identify three additional enzymes of the NAD+ biosynthetic
salvage pathway that perform similar functions in protection against proteotoxic stress: NADS/QNS1,
NaPTRase/NPT1 and NDase/PNC1. These observations suggest the existence of an evolutionarily
conserved strategy of `repurposing' (or `moonlighting') housekeeping enzymes under stress conditions,
and further reveal the intricate balance of metabolic activity and stress response in neurons.
 The main objective of this proposal is to investigate the cytoprotective roles of NAD+
biosynthetic enzymes and mitochondria in normal and proteotoxic environments. We will test the
hypothesis that NAD+ biosynthetic enzymes are a new class of chaperones that perform this function
independently of their catalytic activities and without requiring mitochondrial functions. Furthermore,
we will test whether neuroprotection offered by enhanced mitochondrial biogenesis is additive or
synergistic to protection exerted by the chaperone function of NAD+ biosynthetic enzymes.
 These hypotheses will be investigated in yeast models of polyQ toxicity during yeast
chronological lifespan (CLS), a model of neuronal aging. Furthermore, the results obtained will be
validated in human striatal cells differentiated from induced pluripotent stem cells (iPSCs) derived
from human fibroblasts. Three aims will be pursued: First, we will establish the effectiveness of NAD+
biosynthetic proteins in cellular aging and protection against proteotoxicity. Second, we will perform
structure-function correlation studies to define the domains in NAD+ biosynthetic proteins required for
chaperone or enzymatic activity and their requirement for protection against proteoto...

## Key facts

- **NIH application ID:** 9859319
- **Project number:** 5I01BX003303-04
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** Antoni Barrientos
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859319

## Citation

> US National Institutes of Health, RePORTER application 9859319, Slowing Proteotoxic Neurodegeneration by Boosting Mitochondrial Bioenergetics and Recruiting a Novel Class of Chaperones (5I01BX003303-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9859319. Licensed CC0.

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