Abstract
Mutations in RNA-binding proteins (RBPs) such as TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent evidence suggests that RNA dysregulation mediated by aberrant RBPs may play a critical role in neurodegeneration, but the underlying molecular mechanisms are largely unknown. In this study, we performed whole transcriptome profiling of various brain tissues of a transgenic (Tg) mouse model of ALS/FTD overexpressing the exogenous nuclear localization signal deletion mutant of human FUS (ΔNLS-FUS) to investigate changes associated with the early stages of ALS/FTD. Although there were not many differences in expression profiles between wild-type and Tg mice, we found that Sema3g was significantly upregulated in the frontal cortex and hippocampus of Tg mice. Interestingly, analysis of alternative splicing events identified widespread exons that were differentially regulated in Tg mice in a tissue-specific manner. Our study thus identified aberrant splicing regulation mediated by mutant FUS during the early stages of ALS/FTD. Targeting this aberrant splicing regulation represents a potential therapeutic strategy for ALS/FTD.
Highlights
A landmark discovery in 2006 identified TAR DNA-binding protein 43 (TDP-43) accumulation as a pathological hallmark of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), linking the disease mechanisms of ALS and FTD1,2
Several studies have demonstrated that many RNA-binding proteins (RBPs) with known mutations associated with ALS/FTD accumulate in the cytoplasm of the affected regions of the central nervous system and possibly contribute to the RNA dysregulation implicated in ALS/FTD pathogenesis[3,4,5,6,11]
Our current study provides valuable insights regarding the RNA dysregulation associated with the early stages of ALS/FTD before neuronal loss
Summary
A landmark discovery in 2006 identified TAR DNA-binding protein 43 (TDP-43) accumulation as a pathological hallmark of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), linking the disease mechanisms of ALS and FTD1,2. Further research identified seven ALS-related RNA-binding proteins (RBPs), FUS, TAF15, EWSR1, HNRNPA1, HNRNPA2B1, Matrin-3, and TIA1, that are characteristically deposited in the affected regions of the ALS/FTD brain[3] These studies, along with others, strongly suggested that dysfunction in RNA processing mediated by aberrant RBPs is a key aspect of the neurodegeneration observed in ALS/FTD3–7. Histological and cytological studies of this Tg mouse model indicated that cytoplasmic FUS aggregates sequester mRNA and RNA transporters leading to synaptic and dendritic spine dysfunction resulting in FTD-like phenotypes even before the appearance of neuronal loss. These results suggest that a gain-of-function toxicity caused by cytoplasmic FUS aggregates lead to RNA dysregulation, thereby causing the behavioral and motor dysfunctions observed. We performed this study to examine whether cytoplasmic accumulation of mutant FUS can induce aberrant splicing regulation or changes in RNA expression during the early stages of ALS/FTD in an effort to understand the mechanism of FUS proteinopathy
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