Elevation of the Hsp70 chaperone does not effect toxicity in mouse models of familial amyotrophic lateral sclerosis.
Mutations in copper/zinc superoxide dismutase (SOD1) account for 10-20% of a familial form of amyotrophic lateral sclerosis (ALS). A common feature of SOD1 mutants is abnormal aggregation of the aberrant SOD1 in neurons and glia. We now report that in ALS transgenic mouse models the constitutively expressed heat shock protein 70 (Hsp70) is mislocalized into aggregates together with mutant SOD1 and ubiquitin. Forcing increased synthesis of Hsp70 ameliorates both aggregate formation and toxicity in primary motor neurons in culture. However, chronic increase in an inducible form of Hsp70 to about 10-fold its normal level is shown here not to affect disease course or pathology developed in mice from accumulation of any of three familial ALS causing SOD1 mutants with different underlying biochemical characteristics. Therefore, increasing Hsp70 to a level that is protective in mouse models of acute ischemic insult and selected neurodegenerative disorders is not sufficient to ameliorate mutant SOD1-mediated toxicity.
Liu
Jian
J
Ludwig Institute for Cancer Research and Department of Neurosciences, University of California, San Diego, La Jolla, 92093, USA.
Shinobu
Leslie A
LA
Ward
Christopher M
CM
Young
Darren
D
Cleveland
Don W
DW
D000367:Age Factors; D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology*; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1