# Mechanistic basis for endoplasmic reticulum-driven cytoprotection by selective autophagy in neurons

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $582,240

## Abstract

SUMMARY.
Neurodegenerative diseases, as age-dependent disorders, represent a rising hazard to human health in
America, given the rapidly growing number of seniors in its population. For this reason, the development of novel
therapies to treat neurodegenerative diseases has become a national priority. These disorders are often
characterized by the incorrect folding of certain proteins, accumulation of cytotoxic macromolecular structures,
and changes in intracellular stress response capacity - our proposal aims to identify a means to resolve these
conditions. Numerous labs over the last decade have elucidated mechanisms underlying selective autophagy -
the process by which damaged organelles, protein aggregates, or misfolded proteins are targeted to the
autophagosome for degradation in the lysosome. Our understanding of autophagy is that it controls a large
fraction of regulated protein homeostasis in human cells, particularly post-mitotic cells (i.e., a cell that does not
divide) like neurons. While autophagy is broadly associated with the turnover of proteins or organelles, several
autophagy-related genes have been specifically genetically linked with aging and neurodegenerative cellular
signaling pathways. Despite these advances, our understanding of how neuronal cells use and rely on specific
forms of autophagy via specialized proteins called receptors is incomplete for several reasons. First, most studies
have focused on a small number of well-studied receptors, and systematic approaches aimed at uncovering the
global contribution of known and other possible receptors are lacking, leaving major gaps in our understanding
of the many roles these proteins may play. Second, the majority of studies have focused on processes in cancer
cell lines in culture, and we know very little about the cell type-relevant roles of selective autophagy receptors in
neuronal homeostasis. Third, although we know that selective autophagy receptors are regulated dynamically,
we still have a relatively rudimentary understanding of the signaling pathways that control receptor engagement
in physiological or stress-induced states. Here, we propose a series of experiments that seek to address
limitations in our understanding of the neuronal selective autophagy pathways, their regulation, and their
function. In the first series of experiments (AIM 1), we will build on preliminary data to elucidate the role of an
endoplasmic reticulum membrane-bound receptor we identified to be regulated upon nutrient stress in neurons,
and reveal the molecular mechanisms involved in its regulation and the nature of the substrate turned over. A
second series of experiments (AIM 2) will be focused on investigating the cellular specificity across neuroimmune
cell subtypes, response to pathological cues modeled in iPSCs, and functional and physiological relevance using
knock-out mouse models. Together, these studies will quantitatively, mechanistically, and functionally address
gaps in our unde...

## Key facts

- **NIH application ID:** 10981290
- **Project number:** 1R01NS134891-01A1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Alban Ordureau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $582,240
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981290

## Citation

> US National Institutes of Health, RePORTER application 10981290, Mechanistic basis for endoplasmic reticulum-driven cytoprotection by selective autophagy in neurons (1R01NS134891-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10981290. Licensed CC0.

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