Poly-dipeptides produced from <i>C9orf72</i> hexanucleotide repeats cause selective motor neuron hyperexcitability in ALS.

Abstract

SignificanceThe GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (<i>C9orf72</i>) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS). Despite myriad studies on the toxic effects of poly-dipeptides produced from the <i>C9orf72</i> repeats, the mechanisms underlying the selective hyperexcitability of motor cortex that characterizes the early stages of <i>C9orf72</i> ALS patients remain elusive. Here, we show that the proline-arginine poly-dipeptides cause hyperexcitability in cortical motor neurons by increasing persistent sodium currents conducted by the Nav1.2/β4 sodium channel complex, which is highly expressed in the motor cortex. These findings provide the basis for understanding how the <i>C9orf72</i> mutation causes motor neuron hyperactivation that can lead to the motor neuron death in <i>C9orf72</i> ALS.