# Defining cell type-specific functions for the selective autophagy receptor p62 in neurons and astrocytes

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $17,812

## Abstract

Project Summary. Neurons and astrocytes have unique demands in regulating the quality of their proteome. A
key regulator of the proteome is autophagy, a lysosomal degradation pathway. During autophagy, cytoplasmic
components are packaged into autophagosomes and delivered to lysosomes for cargo degradation.
Autophagy is neuroprotective, as mutations in key autophagy genes cause neurodegeneration. Preliminary
studies show that autophagy is regulated differently in neurons and astrocytes in multiple paradigms of stress.
Despite the importance of autophagy, how it is regulated in neurons and astrocytes to facilitate cell-
type specific functions and stress responses is largely unknown. Thus, the goal for this proposal is to
define cell-type specific functions for the autophagy receptor p62 in neurons and astrocytes. P62 facilitates
selective forms of autophagy by binding to ubiquitinated substrates and the autophagy marker LC3, thereby
incorporating cargo into a forming autophagosome. P62 mitigates proteotoxic stress by targeting protein
aggregates to the autophagy pathway. Additionally, p62 mitigates oxidative stress by targeting Keap1, a
negative regulator of the antioxidant transcription factor NRF2, for degradation by autophagy. To examine
functions of p62 in each cell type, we established a robust system to coculture neuron and astrocytes. This
system recapitulates intercellular interactions found in vivo, and provides an easily manipulatable system for
studying cell-type specific p62 function with high resolution. Using the coculture, I found by immunostain that
metabolic stress (autophagy activator) induces formation of p62-ubiquitin positive structures (i.e., ubiquitinated
cargo) only in neurons. Moreover, blocking ubiquitination significantly reduces p62 puncta formation and
degradation in neurons as compared to astrocytes in basal and stress conditions. Astrocytes are crucial to
combating oxidative stress, but the role of p62 in this pathway in astrocytes is largely unknown. I found that
oxidative stress induces p62 levels selectively in astrocytes. Thus, I hypothesize that p62 functions
primarily in selective autophagy in neurons, and primarily in the antioxidant pathway in astrocytes.
Importantly, ALS-linked mutations in p62 fall in domains important for each function. But how p62 protects
against neurodegeneration in each cell type is not understood. I hypothesize that ALS-linked mutations in
p62 domains that are important for selective autophagy and antioxidant function will impair p62
function in neurons and astrocytes, respectively. To test these hypotheses, I will (Aim 1) define cell-type
specific functions of p62 in neurons and astrocytes, and (Aim 2) determine the effects of ALS-linked mutations
on p62 function in neurons and astrocytes. This study will elucidate cell-type specific contributions of neurons
and astrocytes to neurodegeneration. In turn, understanding cell-type specific contributions to ALS will enable
opportunities f...

## Key facts

- **NIH application ID:** 10934354
- **Project number:** 5F31NS132431-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** DAVID Kader SIDIBE
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $17,812
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934354

## Citation

> US National Institutes of Health, RePORTER application 10934354, Defining cell type-specific functions for the selective autophagy receptor p62 in neurons and astrocytes (5F31NS132431-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10934354. Licensed CC0.

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