Focal degeneration of astrocytes in amyotrophic lateral sclerosis

• Published in: Cell death and differentiation Vol. 15; no. 11; pp. 1691 - 1700
• Main Authors: Rossi, D, Brambilla, L, Valori, C F, Roncoroni, C, Crugnola, A, Yokota, T, Bredesen, D E, Volterra, A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.11.2008
• Subjects: Amino acids; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - pathology; Animals; Astrocytes - drug effects; Astrocytes - enzymology; Astrocytes - pathology; Caspase 3 - metabolism; Cell death; Cell Survival - drug effects; Cytoskeleton - drug effects; Cytoskeleton - metabolism; Disease; Enzyme Activation - drug effects; Glial Fibrillary Acidic Protein - metabolism; Glutamates - pharmacology; Humans; Lumbar Vertebrae - enzymology; Mice; Morphology; Motor Neurons - drug effects; Motor Neurons - enzymology; Motor Neurons - pathology; Mutant Proteins - metabolism; Neurons; Physiology; Proteins; Pyridines - administration & dosage; Pyridines - pharmacology; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Spheroids, Cellular - drug effects; Spheroids, Cellular - enzymology; Spheroids, Cellular - pathology; Spinal cord; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Transgenic animals; Italy
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2008.99

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.