Focal degeneration of astrocytes in amyotrophic lateral sclerosis

D. Rossi, L. Brambilla, C. F. Valori, C. Roncoroni, A. Crugnola, T. Yokota, D. E. Bredesen, A. Volterra

Research output: Contribution to journalArticle

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 hSOD1G93A 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 hSOD1G93A 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.

Original languageEnglish
Pages (from-to)1691-1700
Number of pages10
JournalCell Death and Differentiation
Volume15
Issue number11
DOIs
Publication statusPublished - 2008

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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    Rossi, D., Brambilla, L., Valori, C. F., Roncoroni, C., Crugnola, A., Yokota, T., Bredesen, D. E., & Volterra, A. (2008). Focal degeneration of astrocytes in amyotrophic lateral sclerosis. Cell Death and Differentiation, 15(11), 1691-1700. https://doi.org/10.1038/cdd.2008.99