Increased levels of p70S6 phosphorylation in the G93A mouse model of Amyotrophic Lateral Sclerosis and in valine-exposed cortical neurons in culture.
The higher risk factor for Amyotrophic Lateral Sclerosis (ALS) among Italian soccer players is a question that is still debated. One of the hypotheses that have been formulated to explain a possible link between ALS and soccer players is related to the abuse of dietary supplements and drugs for enhancing sporting performance. In particular, it has been reported that branched-chain amino acids (BCAAs) are widely used among athletes as nutritional supplements. To observe the possible effect of BCAAs on neuronal electrical properties, we performed electrophysiological experiments on Control cultured cortical neurons and on neurons after BCAA treatment. BCAA-treated neurons showed hyperexcitability and rapamycin was able to suppress it and significantly reduce the level of mTOR, Akt and p70S6 phosphorylation. Interestingly, the hyperexcitability previously reported in cortical neurons from a genetic mouse model of ALS (G93A) was also reversed by rapamycin treatment. Moreover, both G93A and valine-treated neurons presented significantly higher levels of Pp70S6 when compared to control neurons, strongly indicating the involvement of this substrate in ALS pathology. Finally, we performed electrophysiological experiments on motor cortex slices from Control and G93A mice and those fed with a BCAA-enriched diet. We observed that neuron excitability was comparable between G93A and BCAA-enriched diet mice, but was significantly higher than in Control mice. These findings, besides strongly indicating that BCAAs specifically induce hyperexcitability, seem to suggest the involvement of p70S6 substrate in ALS pathology.
Carunchio
Irene
I
Department of Neuroscience, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy.
Curcio
Livia
L
Pieri
Massimo
M
Pica
Francesca
F
Caioli
Silvia
S
Viscomi
Maria Teresa
MT
Molinari
Marco
M
Canu
Nadia
N
Bernardi
Giorgio
G
Zona
Cristina
C
D000200:Action Potentials / Q000187:drug effects; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D058570:TOR Serine-Threonine Kinases; D014633:Valine / Q000494:pharmacology*
D000597:Amino Acids, Branched-Chain; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; C000606290:SOD1 protein, human; D015222:Sodium Channels; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D014633:Valine; D020123:Sirolimus