ALS (amyotrophic lateral sclerosis), a fatal motoneuron (motor neuron) disease, occurs in clinically indistinguishable sporadic (sALS) or familial (fALS) forms. Most fALS-related mutant proteins identified so far are prone to misfolding, and must be degraded in order to protect motoneurons from their toxicity. This process, mediated by molecular chaperones, requires proteasome or autophagic systems. Motoneurons are particularly sensitive to misfolded protein toxicity, but other cell types such as the muscle cells could also be affected. Muscle-restricted expression of the fALS protein mutSOD1 (mutant superoxide dismutase 1) induces muscle atrophy and motoneuron death. We found that several genes have an altered expression in muscles of transgenic ALS mice at different stages of disease. MyoD, myogenin, atrogin-1, TGFβ1 (transforming growth factor β1) and components of the cell response to proteotoxicity [HSPB8 (heat shock 22kDa protein 8), Bag3 (Bcl-2-associated athanogene 3) and p62] are all up-regulated by mutSOD1 in skeletal muscle. When we compared the potential mutSOD1 toxicity in motoneuron (NSC34) and muscle (C2C12) cells, we found that muscle ALS models possess much higher chymotryptic proteasome activity and autophagy power than motoneuron ALS models. As a result, mutSOD1 molecular behaviour was found to be very different. MutSOD1 clearance was found to be much higher in muscle than in motoneurons. MutSOD1 aggregated and impaired proteasomes only in motoneurons, which were particularly sensitive to superoxide-induced oxidative stress. Moreover, in muscle cells, mutSOD1 was found to be soluble even after proteasome inhibition. This effect could be associated with a higher mutSOD1 autophagic clearance. Therefore muscle cells seem to manage misfolded mutSOD1 more efficiently than motoneurons, thus mutSOD1 toxicity in muscle may not directly depend on aggregation.
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December 2013
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Conference Article|
November 20 2013
Motoneuronal and muscle-selective removal of ALS-related misfolded proteins
Valeria Crippa;
Valeria Crippa
1
*Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, Italy
†Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Milano, Genova e Roma Tor Vergata
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Mariarita Galbiati;
Mariarita Galbiati
1
*Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, Italy
†Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Milano, Genova e Roma Tor Vergata
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Alessandra Boncoraglio;
Alessandra Boncoraglio
*Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, Italy
†Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Milano, Genova e Roma Tor Vergata
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Paola Rusmini;
Paola Rusmini
*Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, Italy
†Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Milano, Genova e Roma Tor Vergata
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Elisa Onesto;
Elisa Onesto
‡Dipartimento di Neurologia e Laboratorio di Neuroscienze, IRCCS Istituto Auxologico Italiano, 20133 Milan, Italy
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Elisa Giorgetti;
Elisa Giorgetti
*Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, Italy
†Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Milano, Genova e Roma Tor Vergata
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Riccardo Cristofani;
Riccardo Cristofani
*Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, Italy
†Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Milano, Genova e Roma Tor Vergata
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Arianna Zito;
Arianna Zito
*Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, Italy
†Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Milano, Genova e Roma Tor Vergata
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Angela Poletti
Angela Poletti
2
*Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, 20133 Milan, Italy
†Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Milano, Genova e Roma Tor Vergata
2To whom correspondence should be addressed (emailangelo.poletti@unimi.it).
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Publisher: Portland Press Ltd
Received:
June 21 2013
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem Soc Trans (2013) 41 (6): 1598–1604.
Article history
Received:
June 21 2013
Connected Content
A correction has been published:
Motoneuronal and muscle-selective removal of ALS-related misfolded proteins
Citation
Valeria Crippa, Mariarita Galbiati, Alessandra Boncoraglio, Paola Rusmini, Elisa Onesto, Elisa Giorgetti, Riccardo Cristofani, Arianna Zito, Angela Poletti; Motoneuronal and muscle-selective removal of ALS-related misfolded proteins. Biochem Soc Trans 1 December 2013; 41 (6): 1598–1604. doi: https://doi.org/10.1042/BST20130118
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