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Submitted by Shan (Sarah) Chen, MD, News Science Editorial Board
Hexanucleotide (GGGGCC) expansions in C9ORF72 (abbreviated to c9 often) are the most frequent genetic cause of ALS/FTD. Jiang et al focused on the disease mechanisms of this mutation. They evaluated mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Their data showed that chronic 50% reduction of C9ORF72, as reported in c9ALS/FTD patients, was well tolerated without signs of disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction.
Then they studied transgenic mice that express a bacterial artificial chromosome (BAC) carrying the human expanded c9ORF72 gene from a c9ALS patient. These hexanucleotide expansions caused in these mice accumulation of RNA foci and dipeptide-repeat proteins that is age-, repeat-, length-, and expression-level-dependent, resulting in increased anxiety and impaired cognitive function.
Single-dose intrathecal injection of antisense oligonucleotides (ASOs) that target these mutated RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated the behavioral deficits.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating neurodegenerative diseases with distinct clinical symptoms but common pathological features and genetic causes. Several mechanisms have been proposed including loss of c9ORF72 protein function and gain of toxicity. Jiang et al elegantly identified gain of toxicity as a main pathogenesis of GGGGCC-expanded C9ORF72 for ALS/FTD. They also proved the feasibility and effectiveness of antisense oligonucleotides-mediated therapy.
Mouse models for ALS have been desirable for decades. In the same issue of Neuron, Liu et al also reported development of a c9orf72 BAC mouse model that can be used for future research to develop targeted therapies for ALS/FTD. [Neuron. 2016 May 4;90(3):521-34. doi: 10.1016/j.neuron.2016.04.005. Epub 2016 Apr 21. C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Liu Y, Pattamatta A, Zu T, Reid T, Bardhi O, Borchelt DR, Yachnis AT, Ranum LP.]
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