Amyotrophic lateral sclerosis is the most common motor neu-ron disease and is still incurable. The mechanisms leading to theselective motor neuron vulnerability are still not known. The inter-play between motor neurons and astrocytes is crucial in the out-come of the disease. We show that mutant copper-zinc superoxidedismutase (SOD1) overexpression in primary astrocyte cultures isassociated with decreased levels of proteins involved in secretorypathways. This is linked to a general reduction of total secretedproteins, except for specific enrichment in a number of proteins inthe 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 activateunconventional secretory pathways, possibly as a protective mech-anism. This may help limit the formation of intracellular aggre-gates and overcome mutant SOD1 toxicity. We also found thatastrocyte-derived exosomes efficiently transfer mutant SOD1 tospinal neurons and induce selective motor neuron death. We con-clude that the expression of mutant SOD1 has a substantial impacton astrocyte protein secretion pathways, contributing to motorneuron pathology and disease spread.

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 / Basso, Manuela; Pozzi, Silvia; Tortarolo, Massimo; Fiordaliso, Fabio; Bisighini, Cinzia; Pasetto, Laura; Spaltro, Gabriella; Lidonnici, Dario; Gensano, Francesco; Battaglia, Elisa; Bendotti, Caterina; Bonetto, Valentina. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 2013, 288:22(2013), pp. 15699-15711. [10.1074/jbc.M112.425066]

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

Basso, Manuela;
2013-01-01

Abstract

Amyotrophic lateral sclerosis is the most common motor neu-ron disease and is still incurable. The mechanisms leading to theselective motor neuron vulnerability are still not known. The inter-play between motor neurons and astrocytes is crucial in the out-come of the disease. We show that mutant copper-zinc superoxidedismutase (SOD1) overexpression in primary astrocyte cultures isassociated with decreased levels of proteins involved in secretorypathways. This is linked to a general reduction of total secretedproteins, except for specific enrichment in a number of proteins inthe 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 activateunconventional secretory pathways, possibly as a protective mech-anism. This may help limit the formation of intracellular aggre-gates and overcome mutant SOD1 toxicity. We also found thatastrocyte-derived exosomes efficiently transfer mutant SOD1 tospinal neurons and induce selective motor neuron death. We con-clude that the expression of mutant SOD1 has a substantial impacton astrocyte protein secretion pathways, contributing to motorneuron pathology and disease spread.
2013
22
Basso, Manuela; Pozzi, Silvia; Tortarolo, Massimo; Fiordaliso, Fabio; Bisighini, Cinzia; Pasetto, Laura; Spaltro, Gabriella; Lidonnici, Dario; Gensano, Francesco; Battaglia, Elisa; Bendotti, Caterina; Bonetto, Valentina
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 / Basso, Manuela; Pozzi, Silvia; Tortarolo, Massimo; Fiordaliso, Fabio; Bisighini, Cinzia; Pasetto, Laura; Spaltro, Gabriella; Lidonnici, Dario; Gensano, Francesco; Battaglia, Elisa; Bendotti, Caterina; Bonetto, Valentina. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 2013, 288:22(2013), pp. 15699-15711. [10.1074/jbc.M112.425066]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/201171
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