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Focal degeneration of astrocytes in amyotrophic lateral sclerosis

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Title: Focal degeneration of astrocytes in amyotrophic lateral sclerosis
Authors: Rossi, D., Brambilla, L., Valori, C. F., Roncoroni, C., Crugnola, A., Yokota, T., Bredesen, D. E., Volterra, A.
Publication Year: 2025
Collection: Université de Lausanne (UNIL): Serval - Serveur académique lausannois
Subject Terms: amyotrophic lateral sclerosis, apoptosis, astrocyte, excitotoxicity, metabotropic glutamate receptor, Amyotrophic Lateral Sclerosis,pathology, Animals, Astrocytes,drug effects,enzymology,pathology, Caspase 3,metabolism, Cell Survival,drug effects, Cytoskeleton,drug effects,metabolism, Enzyme Activation,drug effects, Glial Fibrillary Acidic Protein,metabolism, Glutamates,pharmacology, Humans, Lumbar Vertebrae,enzymology, Mice, Motor Neurons,drug effects,enzymology,pathology, Mutant Proteins,metabolism, Pyridines,administration & dosage,pharmacology, Receptors, Metabotropic Glutamate,antagonists & inhibitors, Spheroids, Cellular,drug effects,enzymology,pathology, Superoxide Dismutase,metabolism
Description: Astrocytes emerge as key players in motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS). Whether astrocytes cause direct damage by releasing toxic factors or contribute indirectly through the loss of physiological functions is unclear. Here we identify in the hSOD1(G93A) transgenic mouse model of ALS a degenerative process of the astrocytes, restricted to those directly surrounding spinal motor neurons. This phenomenon manifests with an early onset and becomes significant concomitant with the loss of motor cells and the appearance of clinical symptoms. Contrary to wild-type astrocytes, mutant hSOD1-expressing astrocytes are highly vulnerable to glutamate and undergo cell death mediated by the metabotropic type-5 receptor (mGluR5). Blocking mGluR5 in vivo slows down astrocytic degeneration, delays the onset of the disease and slightly extends survival in hSOD1(G93A) transgenic mice. We propose that excitotoxicity in ALS affects both motor neurons and astrocytes, favouring their local interactive degeneration. This new mechanistic hypothesis has implications for therapeutic interventions.Cell Death and Differentiation advance online publication, 11 July 2008; doi:10.1038/cdd.2008.99.
Document Type: article in journal/newspaper
Language: English
ISSN: 1350-9047
Relation: Cell Death & Differentiation; https://iris.unil.ch/handle/iris/247881; serval:BIB_F31FC6B167F1; 000259970500003
DOI: 10.1038/cdd.2008.99
Availability: https://iris.unil.ch/handle/iris/247881
https://doi.org/10.1038/cdd.2008.99
Accession Number: edsbas.5C28E1A1
Database: BASE
Description
Abstract:Astrocytes emerge as key players in motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS). Whether astrocytes cause direct damage by releasing toxic factors or contribute indirectly through the loss of physiological functions is unclear. Here we identify in the hSOD1(G93A) transgenic mouse model of ALS a degenerative process of the astrocytes, restricted to those directly surrounding spinal motor neurons. This phenomenon manifests with an early onset and becomes significant concomitant with the loss of motor cells and the appearance of clinical symptoms. Contrary to wild-type astrocytes, mutant hSOD1-expressing astrocytes are highly vulnerable to glutamate and undergo cell death mediated by the metabotropic type-5 receptor (mGluR5). Blocking mGluR5 in vivo slows down astrocytic degeneration, delays the onset of the disease and slightly extends survival in hSOD1(G93A) transgenic mice. We propose that excitotoxicity in ALS affects both motor neurons and astrocytes, favouring their local interactive degeneration. This new mechanistic hypothesis has implications for therapeutic interventions.Cell Death and Differentiation advance online publication, 11 July 2008; doi:10.1038/cdd.2008.99.
ISSN:13509047
DOI:10.1038/cdd.2008.99