Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons
- 1Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- 2Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 904, U.S.A
- 3Department of Physiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Abstract
Lysosomal damage impairs proteostasis and contributes to neurodegenerative diseases, yet cell-type-specific differences in lysosomal repair remain unclear. Using a neuron-astrocyte coculture system, we compared responses to lysosomal injury induced by a lysosomotropic methyl ester. Both neurons and astrocytes showed lysosomal damage, marked by galectin-3 recruitment to lumenal lysosomal β-galactosides, elevated lysosomal pH, and engagement of lysophagy receptors TAX1BP1 and p62. However, astrocytes showed a preferential recruitment of ESCRT repair machinery to damaged lysosomes. Additionally, the lysosomal membrane reformation pathway regulated by the RAB7-GAP, TBC1D15, was more robustly activated in astrocytes. By contrast, the PITT pathway, mediating lipid transfer between the ER and damaged lysosomes, was engaged in both cell types. Our data reveal a divergence in how neurons and astrocytes mobilize repair pathways to manage lysosomal damage. These data may reflect differences in lysosomal resilience between astrocytes and neurons and inform therapeutic strategies to correct lysosomal dysfunction in neurodegenerative diseases.
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BibTeX
@article{smith2026astrocytes,
title = {{Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons}},
author = {Erin Murphy Smith and Natalí L. Chanaday and Sandra Maday},
journal = {iScience},
year = {2026},
month = aug,
doi = {10.1016/j.isci.2026.116866},
url = {https://doi.org/10.1016/j.isci.2026.116866},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons
AU - Erin Murphy Smith
AU - Natalí L. Chanaday
AU - Sandra Maday
PY - 2026
DA - 2026/08/01
JO - iScience
DO - 10.1016/j.isci.2026.116866
UR - https://doi.org/10.1016/j.isci.2026.116866
AB - Lysosomal damage impairs proteostasis and contributes to neurodegenerative diseases, yet cell-type-specific differences in lysosomal repair remain unclear. Using a neuron-astrocyte coculture system, we compared responses to lysosomal injury induced by a lysosomotropic methyl ester. Both neurons and astrocytes showed lysosomal damage, marked by galectin-3 recruitment to lumenal lysosomal β-galactosides, elevated lysosomal pH, and engagement of lysophagy receptors TAX1BP1 and p62. However, astrocytes showed a preferential recruitment of ESCRT repair machinery to damaged lysosomes. Additionally, the lysosomal membrane reformation pathway regulated by the RAB7-GAP, TBC1D15, was more robustly activated in astrocytes. By contrast, the PITT pathway, mediating lipid transfer between the ER and damaged lysosomes, was engaged in both cell types. Our data reveal a divergence in how neurons and astrocytes mobilize repair pathways to manage lysosomal damage. These data may reflect differences in lysosomal resilience between astrocytes and neurons and inform therapeutic strategies to correct lysosomal dysfunction in neurodegenerative diseases.
SN - 2589-0042
ER -