# Lysosomal NADPH metabolism regulates proteostasis, aging and tauopathy

> **NIH NIH RF1** · BAYLOR COLLEGE OF MEDICINE · 2021 · $1,591,453

## Abstract

Abstract
Protein homeostasis (proteostasis) is crucial for organism fitness, and its disturbance during aging underlies
age-associated neurodegenerative diseases. It is well known that the pathology of Alzheimer’s disease (AD) is
associated with disruption of proteostasis, leading to aggregation of ß-amyloid (Aß) and hyperphosphorylated
Tau. However, it remains unclear the cellular and molecular mechanism by which proteostasis is disrupted by
AD during the aging process. Lysosomes and endoplasmic reticulum (ER) are two groups of organelles that
play crucial roles in regulating cellular homeostasis and organismal health. Lysosomes are highly metabolic
active and contain various enzymes dedicated to the hydrolysis of specific substrates. At the same time,
others’ and our studies also reveal the signaling role of lysosomes, which is tightly linked with the metabolic
status of the lysosome. On the other hand, ER is essential for protein synthesis and utilizes quality control
mechanisms to maintain proteostasis. To date, it remains poorly understood how mechanistically lysosomal
metabolism and signaling regulate ER proteostasis. In our studies using Caenorhabditis elegans, we have
discovered a novel lysosome-to-nucleus retrograde signaling pathway that links lysosomal NADPH metabolism
and ER proteostasis, and also revealed the crucial role of this lysosomal signaling in AD prevention during
aging. Strikingly, this lysosomal signaling pathway carries molecular, cellular and biochemical conservation in
human. In this proposal, we aim to systemically decipher lysosomal and nuclear components of this signaling
pathway in C. elegans, and to elucidate how this pathway controls ER proteostasis and contributes to AD
pathogenesis in the mammalian nervous system. The proposed studies, although designed in animal models
(C. elegans and mice), will set a stage for understanding the role of lysosomal metabolism and lysosomal
signaling in human health and diseases. The successful accomplishment of this project will advance our
current knowledge regarding lysosomal function and signaling in aging and AD, open a new avenue for
understanding AD pathogenesis during aging, and shed light on the prevention and treatment of AD patients in
our current society and future generations.

## Key facts

- **NIH application ID:** 10316880
- **Project number:** 1RF1AG074540-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Weiwei Dang
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,591,453
- **Award type:** 1
- **Project period:** 2021-09-05 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316880

## Citation

> US National Institutes of Health, RePORTER application 10316880, Lysosomal NADPH metabolism regulates proteostasis, aging and tauopathy (1RF1AG074540-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10316880. Licensed CC0.

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