Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.

Overview

Authors: David K. Sidibe¹, Erin M. Smith¹, Maeve L. Spivey¹, Maria C. Vogel¹, Sandra Maday¹

ORCID iDs: Sandra Maday

Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America

Institutions: University of Pennsylvania (United States)

Journal: PloS one, volume 21, issue 4, article e0345890

Dates: received 17 November 2025; accepted 11 March 2026; published online 20 April 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1371/journal.pone.0345890 · PMID 42008552 · PMCID PMC13095109 · OpenAlex W4416332124

Open access: gold, a free copy (OpenAlex)

Preprint: doi:10.1101/2025.11.17.688722

Status: data only

Categories: mouse (organism), cellular / molecular (subfield)

Methods: Evoked potentials, Statistics, fMRI & imaging

MeSH: Adaptor Proteins, Signal Transducing*, Astrocytes*, Neurons*, Stress, Physiological*, Ubiquitin*, Animals, Lysosomes, Mice, Proteotoxic Stress, Sequestosome-1 Protein (* major topic)

Journal subjects: Biology and Life Sciences, Cell Biology, Cellular Types, Animal Cells, Glial Cells, Macroglial Cells, Astrocytes, Neurons, Neuroscience, Cellular Neuroscience, Cellular Structures and Organelles, Lysosomes, Cell Processes, Cellular Stress Responses, Cell Death, Autophagic Cell Death, Biochemistry, Proteins, Post-Translational Modification, Ubiquitination, Antioxidants, Signal Transduction, Cell Signaling, Signaling Cascades, Stress Signaling Cascade

Topic: Autophagy in Disease and Therapy (Epidemiology, Medicine), according to OpenAlex

Funding: National Institutes of Health (F31NS132431, F31NS132453, R01NS110716)

Citations: cited by 1 paper (Europe PMC); 103 references in the paper

Abstract

Sequestosome 1/p62 (hereafter referred to as p62) is a multifunctional protein that orchestrates various cellular stress response pathways including autophagy, proteasome-mediated degradation, antioxidant defense, nutrient sensing, and inflammatory signaling. Mutations in distinct functional domains of p62 are linked with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), underscoring its importance in neural cells. Neurons and astrocytes, two key cell types in the brain, perform distinct roles in brain physiology and thus encounter a unique landscape of cellular stress. However, how p62 is regulated in these cell types in response to various stress modalities remains largely unexplored. Several functions for p62 depend on its engagement with ubiquitinated substrates. Thus, we investigated how the regulation of p62-ubiquitin conjugates differs between neurons and astrocytes exposed to two stress modalities: lysosomal membrane damage and metabolic stress. Lysosomal damage triggered ubiquitin-dependent assembly of p62 puncta in both neurons and astrocytes. In contrast, nutrient deprivation elicited different responses between neurons and astrocytes. Neurons formed p62-ubiquitin structures more prominently and displayed a greater dependence on ubiquitin for p62 clustering. Together, these findings reveal cell-type-specific and stress-specific regulation of p62-ubiquitin conjugates, indicating that neurons and astrocytes can deploy distinct quality control strategies.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

doi:10.5061/dryad.z612jm6s2 — at Dryad; found in DataCite

Data Availability

All relevant data are within the paper and its Supporting information files. The data values underlying the graphs in the paper have been deposited to Dryad. DOI: 10.5061/dryad.z612jm6s2.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 10 MeSH terms, 1 funder, 103 references.

Cite

This paper

Sidibe, D. K., Smith, E. M., Spivey, M. L., Vogel, M. C., & Maday, S. (2026). Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress. PloS one, 21(4), e0345890. https://doi.org/10.1371/journal.pone.0345890

BibTeX

@article{sidibe2026differential, author = {Sidibe, David K. and Smith, Erin M. and Spivey, Maeve L. and Vogel, Maria C. and Maday, Sandra}, title = {{Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress}}, journal = {PloS one}, year = {2026}, month = apr, volume = {21}, number = {4}, pages = {e0345890}, publisher = {PLOS}, issn = {1932-6203}, doi = {10.1371/journal.pone.0345890}, url = {https://doi.org/10.1371/journal.pone.0345890}, pmid = {42008552}, pmcid = {PMC13095109} }

RIS

TY - JOUR AU - Sidibe, David K. AU - Smith, Erin M. AU - Spivey, Maeve L. AU - Vogel, Maria C. AU - Maday, Sandra TI - Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress T2 - PloS one J2 - PLoS One PY - 2026 DA - 2026/04/20 VL - 21 IS - 4 SP - e0345890 SN - 1932-6203 PB - PLOS DO - 10.1371/journal.pone.0345890 UR - https://doi.org/10.1371/journal.pone.0345890 LA - en ER -

CSL-JSON

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