Devlin AC, Burr K, Borooah S, Foster JD, Cleary EM, Geti I, Vallier L, Shaw CE, Chandran S, Miles GB. Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability. Nat Commun. 2015 Jan 12;6:5999. PubMed.
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I think that this is an exciting paper that reconciles the ALS motor neuron hyperexcitability/hypoexcitability dilemma. First, the current study reinforces that hyperexcitability is an intrinsic property of ALS motor neurons. More importantly, this initial hyperexcitability may have led to loss of normal neuronal function (loss of synaptic activity and action potential output), and suggests an exciting possibility: Would ALS motor neurons be protected if normal neuronal function was restored? Another recent study by Wainger et al. suggests that this might hold true (see Wainger et al., 2014). In vitro, the potassium channel activator Retigabine corrects the hyperexcitability phenotype of SOD1(A4V) motor neurons, and improves motor neuron survival.
More interestingly, the hyperexcitable property of motor neurons appears to be a convergent point for ALS, regardless of the disease-causing mutations. Although Devlin et al. speculate that aberrant RNA processing may contribute to motor neuron hyperexcitability, future work that elucidates the mechanistic links between the various ALS mutations and neuronal hyperexcitability would be a big step forward to help identify better drugs to slow down the progression of this motor neuron disease.
References:
Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, Boulting G, Berry JD, Brown RH Jr, Cudkowicz ME, Bean BP, Eggan K, Woolf CJ. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 2014 Apr 10;7(1):1-11. Epub 2014 Apr 3 PubMed.
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