Transcription elongation factor AFF2/FMR2 regulates expression of expanded GGGGCC repeat-containing C9ORF72 allele in ALS/FTD

Yeliz Yuva-Aydemir, Sandra Almeida (), Gopinath Krishnan, Tania F. Gendron and Fen-Biao Gao ()
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Yeliz Yuva-Aydemir: University of Massachusetts Medical School
Sandra Almeida: University of Massachusetts Medical School
Gopinath Krishnan: University of Massachusetts Medical School
Tania F. Gendron: Mayo Clinic Florida
Fen-Biao Gao: University of Massachusetts Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Expanded GGGGCC (G4C2) repeats in C9ORF72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How RNAs containing expanded G4C2 repeats are transcribed in human neurons is largely unknown. Here we describe a Drosophila model in which poly(GR) expression in adult neurons causes axonal and locomotor defects and premature death without apparent TDP-43 pathology. In an unbiased genetic screen, partial loss of Lilliputian (Lilli) activity strongly suppresses poly(GR) toxicity by specifically downregulating the transcription of GC-rich sequences in Drosophila. Knockout of AFF2/FMR2 (one of four mammalian homologues of Lilli) with CRISPR-Cas9 decreases the expression of the mutant C9ORF72 allele containing expanded G4C2 repeats and the levels of repeat RNA foci and dipeptide repeat proteins in cortical neurons derived from induced pluripotent stem cells of C9ORF72 patients, resulting in rescue of axonal degeneration and TDP-43 pathology. Thus, AFF2/FMR2 regulates the transcription and toxicity of expanded G4C2 repeats in human C9ORF72-ALS/FTD neurons.

Date: 2019
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DOI: 10.1038/s41467-019-13477-8

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