title: ALS-related misfolded protein management in motor neurons and muscle cells.
abstract: Amyotrophic Lateral Sclerosis (ALS) is the most common form of adult-onset motor neuron disease. It is now considered a multi-factorial and multi-systemic disorder in which alterations of the crosstalk between neuronal and non-neuronal cell types might influence the course of the disease. In this review, we will provide evidence that dysfunctions of affected muscle cells are not only a marginal consequence of denervation associated to motor neurons loss, but a direct consequence of cell muscle toxicity of mutant SOD1. In muscle, the misfolded state of mutant SOD1 protein, unlike in motor neurons, does not appear to have direct effects on protein aggregation and mitochondrial functionality. Muscle cells are, in fact, more capable than motor neurons to handle misfolded proteins, suggesting that mutant SOD1 toxicity in muscle is not mediated by classical mechanisms of intracellular misfolded proteins accumulation. Several recent works indicate that a higher activation of molecular chaperones and degradative systems is present in muscle cells, which for this reason are possibly able to better manage misfolded mutant SOD1. However, several alterations in gene expression and regenerative potential of skeletal muscles have also been reported as a consequence of the expression of mutant SOD1 in muscle. Whether these changes in muscle cells are causative of ALS or a consequence of motor neuron alterations is not yet clear, but their elucidation is very important, since the understanding of the mechanisms involved in mutant SOD1 toxicity in muscle may facilitate the design of treatments directed toward this specific tissue to treat ALS or at least to delay disease progression.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy; InterUniversity Center on Neurodegenerative Diseases (CIMN), Università degli Studi di Firenze, Roma "Tor Vergata", Genova and Milano, Italy.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Galbiati
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy; InterUniversity Center on Neurodegenerative Diseases (CIMN), Università degli Studi di Firenze, Roma "Tor Vergata", Genova and Milano, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy; InterUniversity Center on Neurodegenerative Diseases (CIMN), Università degli Studi di Firenze, Roma "Tor Vergata", Genova and Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy; InterUniversity Center on Neurodegenerative Diseases (CIMN), Università degli Studi di Firenze, Roma "Tor Vergata", Genova and Milano, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cristofani
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Cicardi
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giorgetti
authors.affiliation: Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Onesto
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Messi
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy; InterUniversity Center on Neurodegenerative Diseases (CIMN), Università degli Studi di Firenze, Roma "Tor Vergata", Genova and Milano, Italy. Electronic address: angelo.poletti@unimi.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D001343:Autophagy; D006801:Humans; D009046:Motor Neurons / Q000473:pathology*; D032342:Muscle Cells / Q000473:pathology*; D057165:Proteostasis Deficiencies / Q000473:pathology*
keywords: ALS; Autophagy; Motor neurons; Muscle cells; Protein quality system