The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS)
Open Access
- 22 June 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 19 (17), 3440-3456
- https://doi.org/10.1093/hmg/ddq257
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.This publication has 51 references indexed in Scilit:
- TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosisNature Genetics, 2008
- TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral SclerosisScience, 2008
- Mutation of SOD1 in ALS: a gain of a loss of functionHuman Molecular Genetics, 2007
- How do ALS-associated mutations in superoxide dismutase 1 promote aggregation of the protein?Trends in Biochemical Sciences, 2007
- Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral SclerosisScience, 2006
- HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cellsHuman Molecular Genetics, 2005
- Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2LHuman Genetics, 2004
- Lessons from models of SOD1-linked familial ALSTrends in Molecular Medicine, 2004
- Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathyNature Genetics, 2004
- Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosisNature, 1993