Astrocyte regional diversity in ALS includes distinct aberrant phenotypes with common and causal pathological processes.

摘要: Astrocytes are major contributors of motor neuron (MN) degeneration in amyotrophic lateral sclerosis (ALS). We investigated whether regional and cell maturation differences influence ALS astrocyte malfunction. Spinal cortical astrocytes from SOD1G93A (mSOD1) 7-day-old mice were cultured for 5 13 days vitro (DIV). Astrocyte aberrancies predominated 13DIV cells with region specificity. mSOD1 showed early morphological changes a predominant reactive inflammatory phenotype, while repressed proteins genes found spinal cells. Inflammatory-associated miRNAs, e.g. miR-155/miR-21/miR-146a, downregulated the first upregulated later ones. Interestingly, depleted miR-155/miR-21/miR-146a small extracellular vesicles (sEVs/exosomes) was common pathological feature. Cortical induced late apoptosis kinesin-1 downregulation NSC-34 MNs, whereas dynein, decreased nNOS synaptic-related genes. Both regional-distinct enhanced iNOS gene expression MNs. provide information on potential contribution to bulbar-vs. spinal-onset pathology, local neuronal dysfunction their shared miRNA-depleted exosome trafficking. These causal features may have therapeutic implications ALS. Future studies should clarify if astrocyte-derived sEVs active players ALS-related neuroinflammation glial activation.