title: Protective effects of heat shock protein 27 in a model of ALS occur in the early stages of disease progression.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder, characterised by progressive motor neuron degeneration and muscle paralysis. Heat shock proteins (HSPs) have significant cytoprotective properties in several models of neurodegeneration. To investigate the therapeutic potential of heat shock protein 27 (HSP27) in a mouse model of ALS, we conducted an extensive characterisation of transgenic mice generated from a cross between HSP27 overexpressing mice and mice expressing mutant superoxide dismutase (SOD1(G93A)). We report that SOD1(G93A)/HSP27 double transgenic mice showed delayed decline in motor strength, a significant improvement in the number of functional motor units and increased survival of spinal motor neurons compared to SOD1(G93A) single transgenics during the early phase of disease. However, there was no evidence of sustained neuroprotection affecting long-term survival. Marked down-regulation of HSP27 protein occurred during disease progression that was not associated with a reduction in HSP27 mRNA, indicating a translational dysfunction due to the presence of mutant SOD1 protein. This study provides further support for the therapeutic potential of HSPs in ALS and other motor neuron disorders.
authors.affiliation: Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College London, Charing Cross Hospital Campus, Fulham Palace Road, London W6 8RF, UK.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Sharp
authors.forename: Mohammed T
authors.initials: MT
authors.lastname: Akbar
authors.forename: Sonia
authors.initials: S
authors.lastname: Bouri
authors.forename: Atsushi
authors.initials: A
authors.lastname: Senda
authors.forename: Kieran
authors.initials: K
authors.lastname: Joshi
authors.forename: Han-Jou
authors.initials: HJ
authors.lastname: Chen
authors.forename: David S
authors.initials: DS
authors.lastname: Latchman
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Wells
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Belleroche
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D016923:Cell Death; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009046:Motor Neurons / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011597:Psychomotor Performance; D012333:RNA, Messenger / Q000378:metabolism; D011930:Reaction Time / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D002795:Choline O-Acetyltransferase