| Summary: | <p>An expanded hexanucleotide repeat in a noncoding region of the <em>C9orf72</em> gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40andpercnt; of familial cases and 7andpercnt; of sporadic ALS in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of patients carrying <em>C9orf72</em> hexanucleotide expansions, differentiated these to functional motor and cortical neurons and performed an extensive phenotypic characterization. In <em>C9orf72</em> iPSC-derived motor neurons, decreased cell survival is correlated with dysfunction in Ca<sup>2+</sup> homeostasis, reduced levels of the anti-apoptotic protein Bcl-2, increased endoplasmic reticulum (ER) stress and reduced mitochondrial membrane potential. Furthermore, <em>C9orf72</em> motor neurons, and also cortical neurons, show evidence of abnormal protein aggregation and stress granule formation. This study is an extensive characterization of iPSC-derived motor neurons as cellular models of ALS carrying <em>C9orf72</em> hexanucleotide repeats, which describes a novel pathogenic link between <em>C9orf72</em> mutations, dysregulation of calcium signalling and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia (FTD).</p>
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