Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons
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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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our data raise the possibility that TBC1D15 localized to mitochondria in neurons treated with LLOMe
Is it possible that under these conditions, neurons transfer damaged mitochondria and/or other cellular material to astrocytes? It could be interesting to do neuron-specific labeling prior to co-culturing to track mitochondria.
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Thus, the lack of robust ESCRT recruitment is not simply attributed to insufficient protein expression in neurons.
I’m curious if you looked at CHMP2B levels by western blot in addition to immunofluorescence. Is it possible that neurons express alternate mRNA isoforms and/or proteoforms (e.g. truncated CHMP2B) that disrupt canonical ESCRT recruitment?
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