1. Transcription elongation factor AFF2/FMR2 regulates expression of expanded GGGGCC repeat-containing C9ORF72 allele in ALS/FTD.
- Author
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Yuva-Aydemir Y, Almeida S, Krishnan G, Gendron TF, and Gao FB
- Subjects
- Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis metabolism, Animals, Axons metabolism, Axons pathology, C9orf72 Protein metabolism, DNA Repeat Expansion, DNA-Binding Proteins, Dipeptides metabolism, Down-Regulation, Drosophila, Drosophila Proteins metabolism, Female, Frontotemporal Dementia metabolism, GC Rich Sequence genetics, Gene Knockout Techniques, Humans, Induced Pluripotent Stem Cells, Locomotion, Male, Middle Aged, Neurons pathology, Nuclear Proteins metabolism, Transcription Factors metabolism, Transcription, Genetic, Amyotrophic Lateral Sclerosis genetics, C9orf72 Protein genetics, Dipeptides genetics, Drosophila Proteins genetics, Frontotemporal Dementia genetics, Neurons metabolism, Nuclear Proteins genetics, Transcription Factors genetics
- Abstract
Expanded GGGGCC (G
4 C2 ) repeats in C9ORF72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How RNAs containing expanded G4 C2 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 G4 C2 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 G4 C2 repeats in human C9ORF72-ALS/FTD neurons.- Published
- 2019
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