# Regulatory mechanisms of lysosomal degradation in neurodegenerative disease

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $429,000

## Abstract

PROJECT SUMMARY
Cells respond to nutrient shortage by activating autophagy, regulated processes of removing unnecessary or
dysfunctional cellular components that allow orderly degradation and recycling of proteins, sugars, and
lipids. While it is well known that starvation induces macroautophagy (often simply referred to as just
autophagy), a process involving the formation of double-membraned structure called autophagosomes, other
autophagic pathways, e.g., endosomal microautophagy, also occur as integral parts of the starvation
response to help the cell cope with the stress caused by the nutrient deficiency. As a key step of autophagy,
protein degradation in the lysosomes is crucial for regeneration of amino acids needed for the synthesis of
essential core proteins that support survival of nutrient-deprived cells. However, how lysosomal degradation
is regulated in response to nutrient deprivation is not clear. We have uncovered a novel regulatory pathway
of lysosomal degradation centered around glutamine hydrolysis by glutaminases and the production of
ammonium. Under fed conditions, the abundance of glutamine supports the ammonium production and in
turn alkalization of the lysosome lumen, which slows down protein degradation by keeping lysosomal
hydrolases in suboptimal conditions. Upon amino acid or glutamine withdrawal, the loss of ammonium
production immediately causes acidification of the lysosomes and acceleration of protein degradation. We
further found that this increase in lysosomal degradation following starvation is facilitated by accelerated
autolysosome formation through activation of Mixed Lineage Kinase Domain Like Pseudokinase (MLKL), a
protein previously mainly known for its role in necroptotic cell death downstream of death receptors and
receptor-interacting serine/threonine-protein kinases 1 and 3 (RIPK1 and RIPK3). We show that starvation
activates MLKL through Ca2+-calmodulin-dependent kinase II (CaMKII) independently of RIPK3 and this
pathway targets the oligomerized MLKL to autophagosomes, instead of plasma membrane, where it
supports phagophore closure, a key step required for the maturation of autophagosomes before they fuse
with lysosomes to form autolysosomes where the breakdown of autophagosome cargoes occurs. We aim to
define the functional significance of this new pathway in neurons where autophagy, including lysosomal
degradation, strongly impacts neuronal cell survival and death (Aim I) and further elucidate how multiple
regulatory mechanisms orchestrate the early response of the cells to amino acid shortage in order to cope
with the stress of starvation (Aim II). Because of the critical involvement of autophagy and lysosomal
dysfunction in many types of neurodegenerative diseases, this exploratory and foundational research,
fostering the early and conceptual stages of a novel regulatory mechanism of autophagy and lysosomal
regulation, will likely lead to breakthroughs in important areas of neuroscience.

## Key facts

- **NIH application ID:** 10354193
- **Project number:** 1R21NS125167-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** MICHAEL X ZHU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2021-09-20 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354193

## Citation

> US National Institutes of Health, RePORTER application 10354193, Regulatory mechanisms of lysosomal degradation in neurodegenerative disease (1R21NS125167-01). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10354193. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*