The roles of Nav1.2 sodium channel in C9orf72 ALS

다국어 초록 (Multilingual Abstract)

Amyotrophic lateral sclerosis (ALS), which is well known as Lou Gehrig’s disease, is a severe selective motor neuron death neurodegenerative disease untreatable. One of the related genes is C9orf72 gene, the most common reason of ALS. In the first intron of that gene, GGGGCC expansion induced five types of hexanucleotide repeat. They are reported that can contribute to not only ALS but also frontotemporal dementia (FTD). Because of this, C9orf72 mutation has come up as a severe issue of neurodegenerative diseases. One of the five poly-dipeptides, proline-arginine (PR) poly-dipeptides are reported most toxic and detected lots of C9orf72 ALS patients. In previous study, I reported that PR poly-dipeptides induced selective hyperexcitability to primary motor cortex layer 5 motor neuron via Nav1.2-β1-β4 complex. Here, I described that PR poly-dipeptides made hyperexcitability time dependently only in primary motor cortex layer 5 pyramidal neurons by modulation persistent sodium current and its effects are irreversible. PR20’s long-term effects to cell’s channel function were toxic and even spontaneous firing was observed. Interestingly, chelating Ca2+ could preventedhyperexcitability induced from PR20 and so do increased persistent sodium current. Moreover, control of redox state prevented excess hyperexcitability which kept increased due to PR20 time dependently. Taken together, this study suggests detail effects of PR20 and a clue which leads a mechanism of PR poly-dipeptides with other related cellular toxic factors.