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A human cellular model of amyotrophic lateral sclerosis

Nature Medicine volume 24, pages 256–257 (2018)Cite this article

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Stem cell–derived human motor neurons were used to investigate the cellular mechanisms underlying C9ORF72-related amyotrophic lateral sclerosis.

For roughly 15 Americans each day, a diagnosis of amyotrophic lateral sclerosis (ALS) foreshadows the progressive loss of neural cells controlling motor function and eventually irreversible muscular paralysis1. More than 40 genes have been associated with this disorder, but an effective treatment for patients with ALS remains elusive2. Recent genomic analyses have identified an intronic repeat (GGGGCC) in the C9ORF72 gene in approximately 10% of individuals with ALS, making it the most commonly known genetic cause of ALS3. Moreover, GGGGCC intronic repeats in C9ORF72 are also the most frequent genetic cause of frontotemporal dementia (FTD), which is present in ∼50% of individuals with ALS. The physiological role of C9ORF72 in healthy cells is still unknown, and studies in postmortem samples and animal models have led to discussions as to whether individuals develop ALS because of a reduction in levels of C9ORF72, a loss-of-function mechanism, or through the presence of transcripts with the expanded GGGGCC repeat4, a gain-of-function mechanism. Shi et al.5 explore the role of C9ORF72 in human motor neurons and find evidence for both mechanisms.

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Figure 1: Intronic repeats in C9ORF72 cause loss of human motor neurons.

Marina Corral Spence/Springer Nature

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Authors and Affiliations

  1. the Program in Stem Cell Biology and Regenerative Medicine and the Department of Psychiatry and Behavioral Sciences at Stanford University, Stanford, California, USA

    Rebecca M Marton

  2. Department of Psychiatry and Behavioral Sciences at Stanford University, Stanford, California, USA

    Sergiu P Paşca

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  1. Rebecca M Marton
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  2. Sergiu P Paşca
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Correspondence to Sergiu P Paşca.

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The authors declare no competing financial interests.

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Marton, R., Paşca, S. A human cellular model of amyotrophic lateral sclerosis. Nat Med 24, 256–257 (2018). https://doi.org/10.1038/nm.4509

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