Abstract
Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. The molecular mechanisms underlying disease pathogenesis remain largely unknown. Multiple genetic loci including genes involved in proteostasis and ribostasis have been linked to ALS providing key insights into the molecular mechanisms underlying disease. In particular, the identification of the RNA binding proteins TDP-43 and fused in sarcoma (FUS) as causative factors of ALS resulted in a paradigm shift centered on the study of RNA dysregulation as a major mechanism of disease. With wild-type TDP-43 pathology being found in ~97% of ALS cases and the identification of disease causing mutations within its sequence, TDP-43 has emerged as a prominent player in ALS. More recently, studies of the newly discovered C9orf72 repeat expansion are lending further support to the notion of defects in RNA metabolism as a key factor underlying ALS. RNA binding proteins are involved in all aspects of RNA metabolism ranging from splicing, transcription, transport, storage into RNA/protein granules, and translation. How these processes are affected by disease-associated mutations is just beginning to be understood. Considerable work has gone into the identification of splicing and transcription defects resulting from mutations in RNA binding proteins associated with disease. More recently, defects in RNA transport and translation have been shown to be involved in the pathomechanism of ALS. A central hypothesis in the field is that disease causing mutations lead to the persistence of RNA/protein complexes known as stress granules. Under times of prolonged cellular stress these granules sequester specific mRNAs preventing them from translation, and are thought to evolve into pathological aggregates. Here we will review recent efforts directed at understanding how altered RNA metabolism contributes to ALS pathogenesis.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease
Expression of the transport granule components and translational regulators FMRP and CPEB3, as well as PSD-95, a known FMRP target are increased in C9 induced pluripotent stem cell (iPSC) neurons which suggests that G4C2 incorporation into these granules may affect neuritic mRNA localization and local translation (Burguete et al, 2015)
TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS) and C9orf72 may affect all aspect of RNA metabolism, it is important to note that the effects are likely multi-factorial
Summary
Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease. Multiple other genetic loci have been linked to ALS including those involved in proteostasis, cytoskeletal organization and RNA metabolism (Robberecht and Philips, 2013; Peters et al, 2015). Several other RNA binding (e.g., senataxin, hnRNPA1 Chen et al, 2004; Kim et al, 2013) or stress granule associated proteins (e.g., TIA-1, profilin LiuYesucevitz et al, 2010; Wu et al, 2012; Figley et al, 2014) have been linked to ALS/FTD, here we will address some of these questions by reviewing recent literature on RNA metabolism in ALS and discuss how dysregulation of RNA processing steps may contribute to disease from the perspective of three critically important genes, namely TARDP, FUS and C9orf (Figure 1)
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