title: Specific induction of Akt3 in spinal cord motor neurons is neuroprotective in a mouse model of familial amyotrophic lateral sclerosis.
abstract: Evidence is accumulating that an imbalance between pathways for degeneration or survival in motor neurons may play a central role in mechanisms that lead to neurodegeneration in amyotrophic lateral sclerosis (ALS). We and other groups have observed that downregulation, or lack of induction, of the PI3K/Akt prosurvival pathway may be responsible for defective response of motor neurons to injury and their consequent cellular demise. Some of the neuroprotective effects mediated by growth factors may involve activation of Akt, but a proof of concept of Akt as a target for therapy is lacking. We demonstrate that specific expression of constitutively activated Akt3 in motor neurons through the use of the promoter of homeobox gene Hb9 prevents neuronal loss induced by SOD1.G93A both in vitro (in mixed neuron/astrocyte cocultures) and in vivo (in a mouse model of ALS). Inhibition of ASK1 and GSK3beta was involved in the neuroprotective effects of activated Akt3, further supporting the hypothesis that induction of Akt3 may be a key step in activation of pathways for survival in the attempt to counteract motor neuronal degeneration in ALS.
authors.affiliation: Laboratory of Molecular Neurobiology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, 20156, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Peviani
authors.forename: Massimo
authors.initials: M
authors.lastname: Tortarolo
authors.forename: Elisa
authors.initials: E
authors.lastname: Battaglia
authors.forename: Roberto
authors.initials: R
authors.lastname: Piva
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002470:Cell Survival / Q000235:genetics; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics; D013116:Spinal Cord / Q000201:enzymology* / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt