title: Differential autophagy power in the spinal cord and muscle of transgenic ALS mice.
abstract: Amyotrophic lateral sclerosis (ALS) is a motoneuron disease characterized by misfolded proteins aggregation in affected motoneurons. In mutant SOD1 (mutSOD1) ALS models, aggregation correlates to impaired functions of proteasome and/or autophagy, both essential for the intracellular chaperone-mediated protein quality control (PQC), and to a reduced mutSOD1 clearance from motoneurons. Skeletal muscle cells are also sensitive to mutSOD1 toxicity, but no mutSOD1 aggregates are formed in these cells, that might better manage mutSOD1 than motoneurons. Thus, we analyzed in spinal cord and in muscle of transgenic (tg) G93A-SOD1 mice at presymptomatic (PS, 8 weeks) and symptomatic (S, 16 weeks) stages, and in age-matched control mice, whether mutSOD1 differentially modulates relevant PQC players, such as HSPB8, BAG3, and BAG1. Possible sex differences were also considered. No changes of HSPB8, BAG3, and BAG1 at PS stage (8 weeks) were seen in all tissues examined in tg G93A-SOD1 and control mice. At S stage (16 weeks), HSPB8 dramatically increased in skeletal muscle of tg G93A-SOD1 mice, while a minor increase occurred in spinal cord of male, but not female tg G93A-SOD1 mice. BAG3 expression increased both in muscle and spinal cord of tg G93A-SOD1 mice at S stage, BAG1 expression increased only in muscle of the same mice. Since, HSPB8-BAG3 complex assists mutSOD1 autophagic removal, we analyzed two well-known autophagic markers, LC3 and p62. Both LC3 and p62 mRNAs were significantly up-regulated in skeletal muscle of tg G93A-SOD1 mice at S stage (16 weeks). This suggests that mutSOD1 expression induces a robust autophagic response specifically in muscle. Together these results demonstrate that, in muscle mutSOD1-induced autophagic response is much higher than in spinal cord. In addition, if mutSOD1 exerts toxicity in muscle, this may not be mediated by misfolded proteins accumulation. It remains unclear whether in muscle mutSOD1 toxicity is related to aberrant autophagy activation.
authors: Sezione di Biomedicina e Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano Milano, Italy ; Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze Milano, Genova e Roma Tor Vergata, Italy.
authors: Valeria
authors: V
authors: Crippa
authors: Alessandra
authors: A
authors: Boncoraglio
authors: Mariarita
authors: M
authors: Galbiati
authors: Tanya
authors: T
authors: Aggarwal
authors: Paola
authors: P
authors: Rusmini
authors: Elisa
authors: E
authors: Giorgetti
authors: Riccardo
authors: R
authors: Cristofani
authors: Serena
authors: S
authors: Carra
authors: Maria
authors: M
authors: Pennuto
authors: Angelo
authors: A
authors: Poletti
keywords: BAG1; BAG3; HSPB8; amyotrophic lateral sclerosis; autophagy; motoneurons; protein quality control