Abstract
ABSTRACTThe expanded GGGGCC repeat mutation in the C9orf72 gene is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion is transcribed to sense and antisense RNA, which form RNA foci and bind cellular proteins. This mechanism of action is considered cytotoxic. Translation of the expanded RNA transcripts also leads to the accumulation of toxic dipeptide repeat proteins (DPRs). The RNA-binding protein splicing factor proline and glutamine rich (SFPQ), which is being increasingly associated with ALS and FTD pathology, binds to sense RNA foci. Here, we show that SFPQ plays an important role in the C9orf72 mutation. Overexpression of SFPQ resulted in higher numbers of both sense and antisense RNA foci and DPRs in transfected human embryonic kidney (HEK) cells. Conversely, reduced SPFQ levels resulted in lower numbers of RNA foci and DPRs in both transfected HEK cells and C9orf72 mutation-positive patient-derived fibroblasts and lymphoblasts. Therefore, we have revealed a role of SFPQ in regulating the C9orf72 mutation that has implications for understanding and developing novel therapeutic targets for ALS and FTD.This article has an associated First Person interview with the first author of the paper.
Highlights
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders
SFPQ does not bind antisense RNA in vitro First, we investigated whether SFPQ interacts with antisense RNA in vitro, as is the case for sense RNA (Bajc Č esnik et al, 2019), by performing a RNA pull-down assay on mouse brain lysates
SFPQ did not bind to the (C4G2)32 RNA repeats, as the signal for SFPQ was 0.66± 0.33 relative to control S1m construct, whereas SFPQ did bind to the (G4C2)48 RNA repeats, as the signal increased to 29.94±4.04 of the control (Fig. 1; Fig. S1)
Summary
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders. Up to 20–25 of these repeats are present in healthy individuals, whereas up to several thousand repeats occur in C9orf ALS and FTD patients (DeJesus-Hernandez et al, 2011; Gao et al, 2017; Renton et al, 2011) These repeats form secondary structures, such as G-quadruplexes, hairpins and i-motifs, both at the DNA and RNA level (Božič et al, 2020; Haeusler et al, 2014; Kovanda et al, 2016; Šket et al, 2015). The abovementioned mechanisms of action of the C9orf mutation are predicted to act in synergy to provoke disease-relevant phenotypes, as opposed to only one of the described mechanisms playing the predominant role (Balendra and Isaacs, 2018; Haeusler et al, 2016)
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