Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motoneurons of the spinal cord and motor cortex die, resulting in progressive paralysis. This condition has no cure and results in eventual death, usually within 1-5 years of diagnosis. Although the specific etiology of ALS is unknown, 20% of familial cases of the disease carry mutations in the gene encoding Cu/Zn superoxide dismutase-1 (SOD1). Transgenic mice overexpressing human mutant SOD1 have a phenotype and pathology that are very similar to that seen in human ALS patients. Here we show that treatment with arimoclomol, a coinducer of heat shock proteins (HSPs), significantly delays disease progression in mice expressing a SOD1 mutant in which glycine is substituted with alanine at position 93 (SOD1(G93A)). Arimoclomol-treated SOD1(G93A) mice show marked improvement in hind limb muscle function and motoneuron survival in the later stages of the disease, resulting in a 22% increase in lifespan. Pharmacological activation of the heat shock response may therefore be a successful therapeutic approach to treating ALS, and possibly other neurodegenerative diseases.
Kieran
Dairin
D
The Graham Watts Laboratory, Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, University College London, Queen Square, London WC1N 3BG, UK.
Kalmar
Bernadett
B
Dick
James R T
JR
Riddoch-Contreras
Joanna
J
Burnstock
Geoffrey
G
Greensmith
Linda
L
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D018450:Disease Progression; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics
D006360:Heat-Shock Proteins; D006898:Hydroxylamines; D013482:Superoxide Dismutase; C486387:arimoclomol