title: The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS).
abstract: Several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), are characterized by the presence of misfolded proteins, thought to trigger neurotoxicity. Some familial forms of ALS (fALS), clinically indistinguishable from sporadic ALS (sALS), are linked to superoxide dismutase 1 (SOD1) gene mutations. It has been shown that the mutant SOD1 misfolds, forms insoluble aggregates and impairs the proteasome. Using transgenic G93A-SOD1 mice, we found that spinal cord motor neurons, accumulating mutant SOD1 also over-express the small heat shock protein HspB8. Using motor neuronal fALS models, we demonstrated that HspB8 decreases aggregation and increases mutant SOD1 solubility and clearance, without affecting wild-type SOD1 turnover. Notably, HspB8 acts on mutant SOD1 even when the proteasome activity is specifically blocked. The pharmacological blockage of autophagy resulted in a dramatic increase of mutant SOD1 aggregates. Immunoprecipitation studies, performed during autophagic flux blockage, demonstrated that mutant SOD1 interacts with the HspB8/Bag3/Hsc70/CHIP multiheteromeric complex, known to selectively activate autophagic removal of misfolded proteins. Thus, HspB8 increases mutant SOD1 clearance via autophagy. Autophagy activation was also observed in lumbar spinal cord of transgenic G93A-SOD1 mice since several autophago-lysosomal structures were present in affected surviving motor neurons. Finally, we extended our observation to a different ALS model and demonstrated that HspB8 exerts similar effects on a truncated version of TDP-43, another protein involved both in fALS and in sALS. Overall, these results indicate that the pharmacological modulation of HspB8 expression in motor neurons may have important implications to unravel the molecular mechanisms involved both in fALS and in sALS.
authors.affiliation: Dipartimento di Endocrinologia, Fisiopatologia e Biologia Applicata (Center of Excellence on Neurodegenerative Diseases, CEND), Università degli Studi di Milano, Milano, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.forename: Daniela
authors.initials: D
authors.lastname: Sau
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boncoraglio
authors.forename: Elisa
authors.initials: E
authors.lastname: Onesto
authors.forename: Elena
authors.initials: E
authors.lastname: Bolzoni
authors.forename: Mariarita
authors.initials: M
authors.lastname: Galbiati
authors.forename: Elena
authors.initials: E
authors.lastname: Fontana
authors.forename: Marianna
authors.initials: M
authors.lastname: Marino
authors.forename: Serena
authors.initials: S
authors.lastname: Carra
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.forename: Silvia
authors.initials: S
authors.lastname: De Biasi
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D050886:HSP20 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009046:Motor Neurons / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D004268:DNA-Binding Proteins; D050886:HSP20 Heat-Shock Proteins; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; C490206:Hspb8 protein, mouse; D018832:Molecular Chaperones; D009124:Muscle Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D017346:Protein Serine-Threonine Kinases