title: Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis is the most common motor neuron disease and is still incurable. The mechanisms leading to the selective motor neuron vulnerability are still not known. The interplay between motor neurons and astrocytes is crucial in the outcome of the disease. We show that mutant copper-zinc superoxide dismutase (SOD1) overexpression in primary astrocyte cultures is associated with decreased levels of proteins involved in secretory pathways. This is linked to a general reduction of total secreted proteins, except for specific enrichment in a number of proteins in the media, such as mutant SOD1 and valosin-containing protein (VCP)/p97. Because there was also an increase in exosome release, we can deduce that astrocytes expressing mutant SOD1 activate unconventional secretory pathways, possibly as a protective mechanism. This may help limit the formation of intracellular aggregates and overcome mutant SOD1 toxicity. We also found that astrocyte-derived exosomes efficiently transfer mutant SOD1 to spinal neurons and induce selective motor neuron death. We conclude that the expression of mutant SOD1 has a substantial impact on astrocyte protein secretion pathways, contributing to motor neuron pathology and disease spread.
authors.affiliation: Dulbecco Telethon Institute, Milano, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Basso
authors.forename: Silvia
authors.initials: S
authors.lastname: Pozzi
authors.forename: Massimo
authors.initials: M
authors.lastname: Tortarolo
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.forename: Cinzia
authors.initials: C
authors.lastname: Bisighini
authors.forename: Laura
authors.initials: L
authors.lastname: Pasetto
authors.forename: Gabriella
authors.initials: G
authors.lastname: Spaltro
authors.forename: Dario
authors.initials: D
authors.lastname: Lidonnici
authors.forename: Francesco
authors.initials: F
authors.lastname: Gensano
authors.forename: Elisa
authors.initials: E
authors.lastname: Battaglia
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.forename: Valentina
authors.initials: V
authors.lastname: Bonetto
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000201:enzymology* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D055354:Exosomes / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse
keywords: Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease); Astrocytes; Disease Spreading; Exosomes; Proteomics; Superoxide Dismutase (SOD)