Failure to Deliver and Translate—New Insights into RNA Dysregulation in ALS

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.

To Be or Not To Be…Toxic—Is RNA Association With TDP-43 Complexes Deleterious or Protective in Neurodegeneration?

“…Furthermore, 2-4% of ALS patients harbor mutations in TDP-43, which together with the presence of wildtype TDP-43 in pathological aggregates highlight its role as a common denominator for the majority of ALS cases and a significant fraction of related neurodegenerative disorders. Since its discovery in 2006 as a major component of pathological aggregates, we have learned a great deal about the involvement of TDP-43 in several steps of RNA processing including transcription, splicing, RNA stability, transport, localization, and translation, with several excellent reviews being recently written on the role of TDP-43 in these processes (Bowden and Dormann, 2016;Coyne et al, 2017b;Butti and Patten, 2018;Lehmkuhl and Zarnescu, 2018;Afroz et al, 2019;Birsa et al, 2019;Hergesheimer et al, 2019); however, its precise involvement in disease remains to be elucidated. Despite the presence of two RNA binding domains (RNA Recognition Motifs, RRM1 and 2) within its structure ) and numerous reports of binding to specific RNA sequences and mRNA targets (Polymenidou et al, 2011;Sephton et al, 2011;Tollervey et al, 2011;Arnold et al, 2013), the significance of RNA association with TDP-43 and its contribution to disease pathology remains a topic of debate.…”

Dynamic duo – FMRP and TDP-43: Regulating common targets, causing different diseases

“…In neuroblastoma cells, TDP-43 interacts directly with ribosomes via RACK1, which impacts translation globally and may have implications in disease (Russo et al, 2017). In summary, evidence is increasingly supporting the notion that TDP-43 proteinopathy results from perturbations in RBP partners interactions (Blokhuis et al, 2016) and RNA processing at multiple steps including RNA splicing, non-coding RNA metabolism, miRNA biogenesis, stress granule formation and translation (recently reviewed in Coyne et al, 2017b). More structural studies are needed to understand how the different domains of TDP-43 may interact with each other and whether the low complexity C terminus domain where the majority of disease associated mutations reside impacts RNA binding and/or interactions with partner proteins.…”

Repeat-associated non-ATG (RAN) translation

“…Furthermore, C9ORF72 knockout mice display an altered immune response but do not develop motor neuron degeneration or other features of ALS or FTD (98 -103), suggesting loss-of-function of C9ORF72 is not a primary driver of disease. Data supporting an RNA gain-of-function mechanism includes the accumulation of both sense and antisense RNA foci in C9 patients and various model systems (35,75,104), splicing defects in C9 patient cells (105)(106)(107), and the in vitro identification of multiple potential C9ORF72 RNAbinding proteins (96, 104, 108 -116). These findings, particularly the C9-associated RNA-binding proteins, have shown considerable variability leaving the contributions of specific RBPs in disease unclear.…”