# Molecular mechanisms that match lysosome function to cellular demand

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $343,375

## Abstract

Project Summary/Abstract
Lysosomes serve as a major site for the degradation of macromolecules and play a central role in the ability of
cells to sense and respond to changes in intracellular nutrient availability. Conversely, levels of intracellular
nutrients such as amino acids regulate lysosomal properties, including their biogenesis, acidification, signaling
functions and subcellular position. Defining the molecular machinery that allows for this coordination of
lysosome function with nutrient availability is critical for unraveling how lysosome homeostasis is maintained in
health and disease. This project focuses on a heterotrimeric protein complex made up of C9orf72, SMCR8 and
WDR41. Our interest in this protein complex stems from our discoveries that it is recruited to lysosomes upon
amino acid deprivation and is required for both degradative functions of lysosomes as well as their ability to
support activation of mTORC1 in response to acute exposure to amino acids. Our proposed research thus
seeks to: 1) Elucidate the mechanisms whereby cells couple the sensing of changes in amino acid availability
to the recruitment of C9orf72-SMCR8-WDR41 to lysosomes. 2) Define the direct lysosomal targets of C9orf72-
SMCR8-WDR41. 3) Establish how this overall pathway is integrated into the maintenance of lysosome
homeostasis. While our research focuses on using human cellular models to determine the essential
lysosome-related functions of this protein complex, we anticipate that our findings will have broad relevance for
understanding how cells respond to lysosome dysfunction in both normal physiology and disease. In particular,
expansion of a hexanucleotide repeat in a non-coding region of the C9orf72 gene is the most common familial
cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) identified to date. The current
lack of understanding of C9orf72 protein function is a major obstacle to understanding the potential impact of
reduced C9orf72 protein levels in the development of these neurodegenerative diseases. The results of our
experiments are expected to yield direct targets of C9orf72 and will thereby provide a foundation for the
evaluation of their dysregulation in the context of neurodegenerative disease. Beyond addressing specific
questions about C9orf72 protein function and neurodegenerative disease, elucidation of fundamental
mechanisms that match lysosome function to ongoing changes in cellular demand is of broad cell biological
importance with potential relevance for multiple physiological and pathological contexts.

## Key facts

- **NIH application ID:** 10093058
- **Project number:** 5R01GM105718-08
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** SHAWN FERGUSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $343,375
- **Award type:** 5
- **Project period:** 2013-09-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093058

## Citation

> US National Institutes of Health, RePORTER application 10093058, Molecular mechanisms that match lysosome function to cellular demand (5R01GM105718-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10093058. Licensed CC0.

---

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