TDP-43 mutations increase HNRNP A1-7B through gain of splicing function

Abstract

In a recent investigation Deshaies and colleagues identify HNRNP A1-7B, an isoform of the RNA binding protein (RBP) HNRNP A1, as present in post mortem amyotrophic lateral sclerosis (ALS) spinal motor neuron inclusions (Deshaies et al., 2018). HNRNP A1 is an important player in ALS, as mutations in its low complexity domain (LCD) can be causative for the disease (Kim et al., 2013). Intriguingly, the isoform described by Deshaies et al.includes exon 7B, which produces an extension of the LCD by 52 amino acids, pointing to a link between this alternative splicing event and neuronal protein aggregation. The authors further suggest that loss of RBP TDP-43 can influence this splicing event and result in an increase of the aggregation-prone 7B isoform. TDP-43 is abnormally mislocalised in >95% of ALS cases and when mutated can cause ALS (Harrison and Shorter, 2017). TDP-43 binds RNA, preferentially at UG repeats, and is involved in alternative splicing (Buratti and Baralle, 2001). Importantly, its activity is extremely dosage sensitive, making physiological expression an essential condition for studying the effect of TDP-43 mutations on splicing. Recently, we and others have published an allelic series of novel physiological TDP-43 mouse mutant models and shown that C-terminal mutations induce RNA splicing gain of function (Fratta et al., 2018; White et al., 2018). In order to investigate the link between TDP-43, its mutations and Hnrnpa1 exon 7B splicing, we utilised recently published

Anti-Epileptic Potential of Ziziphus Vulgaris and Ferula Asafoetida Extracts in Drug Induced Seizure Models of Experimental Mice

“…In addition, ZV & FA extracts showed more protection against seizures and mortality in picrotoxin-induced seizure model as compared to strychnine-induced seizure model at high doses (Figure 3). [44,45]. Future studies could be designed to determine the GABAergic potential of these extracts for better mechanistic insights.…”

Reply: TDP-43 mutations increase HNRNP A1-7B through gain of splicing function

“…We appreciate the interest taken by Dr Fratta and his team (Sivakumar et al, 2018) in our recent work documenting the impact of TDP-43 on the splicing of hnRNP A1 and its potential relevance in the pathogenesis of amyotrophic lateral sclerosis (ALS) as outlined in our paper 'TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis' (Deshaies et al, 2018). Indeed, their letter highlights the complexity of RNA binding protein (RBP) functional networks.…”

Natural and pathogenic protein sequence variation affecting prion-like domains within and across human proteomes

“…Under the current model for prionlike aggregation, the high-scoring protein isoform (which is typically less-abundant than the low-scoring isoform [88,89]) could "seed" protein aggregates, which may then be capable of recruiting the lower-scoring isoform. Although this is currently speculative, it is supported by a recent study, which showed that mutation in the TDP-43 PrLD and cytoplasmic aggregation of TDP-43 in ALS patients was associated with dysregulation of hnRNPA1 mRNA splicing [89,90]. This dysregulation led to increased abundance of the high-scoring hnRNPA1-B isoform and subsequent aggregation of the hnRNPA1 protein [89].…”