Vascular endothelial growth factor counteracts the loss of phospho-Akt preceding motor neurone degeneration in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that results in the selective loss of motor neurones. In the present study, the involvement of the antiapoptotic protein, Akt (protein kinase B), was studied. We found that motor neurones of both sporadic and familial ALS patients lack phospho-Akt, and that motor neurones of mutant SOD1 mice lose activated Akt early in the disease, before the onset of clinical symptoms. In vitro, overexpression of constitutively active Akt protects against mutant SOD1-dependent cell death. In vivo, levels of phospho-Akt in the spinal cord increase after intracerebroventricular administration of vascular endothelial growth factor to mutant SOD1 rats, a treatment we previously described to significantly protect motor neurones. From these results, we conclude that the loss of phospho-Akt could be involved in motor neurone death in ALS, and that therapies upregulating phospho-Akt thus might be of clinical relevance.
Dewil
M
M
Laboratory for Neurobiology, Experimental Neurology, University of Leuven, Campus Gasthuisberg, Leuven, Belgium.
Lambrechts
D
D
Sciot
R
R
Shaw
P J
PJ
Ince
P G
PG
Robberecht
W
W
Van den Bosch
L
L
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
D018696:Neuroprotective Agents; C000606290:SOD1 protein, human; D042461:Vascular Endothelial Growth Factor A; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D051057:Proto-Oncogene Proteins c-akt