Abstract
Expanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved. One proposed gain-of-function mechanism is that repeat-containing RNA forms aggregates that sequester RNA binding proteins, leading to altered RNA metabolism in motor neurons. Here, we identify the zinc finger protein Zfp106 as a specific GGGGCC RNA repeat-binding protein, and using affinity purification-mass spectrometry, we show that Zfp106 interacts with multiple other RNA binding proteins, including the ALS-associated factors TDP-43 and FUS. We also show that Zfp106 knockout mice develop severe motor neuron degeneration, which can be suppressed by transgenic restoration of Zfp106 specifically in motor neurons. Finally, we show that Zfp106 potently suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Thus, these studies identify Zfp106 as an RNA binding protein with important implications for ALS.
Highlights
Expanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesusHernandez et al, 2011; Renton et al, 2011)
One idea suggests that toxic dipeptide repeat (DPR) proteins generated by repeat associated non-ATG (RAN) translation of the RNA repeats cause neurodegeneration (Kwon et al, 2014; Mizielinska et al, 2014; Mori et al, 2013)
Sequestration of RNA binding proteins by rGGGGCC repeats has been implicated in the pathology of C9orf72 ALS (Mizielinska and Isaacs, 2014)
Summary
Expanded GGGGCC repeats in the first intron of the C9orf gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesusHernandez et al, 2011; Renton et al, 2011). The human ortholog, ZNF106, is located at human chromosome 15q15.1 (Chr15: 42,412,437– 42,491,197; Genome Reference Consortium Human Build 38), a region with strong linkage to a rare recessive familial form of ALS (Hentati et al, 1998), suggesting a possible role in human ALS. Consistent with this notion, mice lacking Zfp106 function show evidence of nondevelopmental neuromuscular degeneration, suggestive of a possible role for Zfp106 in ALS (Anderson et al, 2016; Joyce et al, 2016; van der Weyden et al, 2011). These studies have important implications for the most common form of human ALS
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