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Specific Induction of Akt3 in Spinal Cord Motor Neurons is Neuroprotective in a Mouse Model of Familial Amyotrophic Lateral Sclerosis

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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.

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Acknowledgments

We wish to acknowledge the financial support of Istituto Superiore di Sanità, project no. 526D/6: “Projects on rare diseases funded within the bilateral agreement Italy (Istituto Superiore di Sanità) and USA (NIH, Office for Rare Disesases) on joint research and development of public health actions,” the FP6 STREP EU grant (no. 12702) and Italian ALS association (AISLA).

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  1. Laboratory of Molecular Neurobiology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, 20156, Milan, Italy

    Marco Peviani, Massimo Tortarolo, Elisa Battaglia & Caterina Bendotti

  2. Department of Molecular Biotechnology and Health Science, Center for Experimental Research and Medical Studies (CERMS), University of Turin, Turin, Italy

    Roberto Piva

  3. Laboratory of Cellular and Molecular Neuropharmacology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy

    Marco Peviani

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  1. Marco Peviani
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Correspondence to Caterina Bendotti.

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Peviani, M., Tortarolo, M., Battaglia, E. et al. Specific Induction of Akt3 in Spinal Cord Motor Neurons is Neuroprotective in a Mouse Model of Familial Amyotrophic Lateral Sclerosis. Mol Neurobiol 49, 136–148 (2014). https://doi.org/10.1007/s12035-013-8507-6

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