The era of cryptic exons: implications for ALS-FTD

Abstract

TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, including the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum and a significant fraction of Alzheimer's disease. There are currently no directed disease-modifying therapies for TDP-43 proteinopathies, and no way to distinguish who is affected before death. It is now clear that TDP-43 proteinopathy leads to a number of molecular changes, including the de-repression and inclusion of cryptic exons. Importantly, some of these cryptic exons lead to the loss of crucial neuronal proteins and have been shown to be key pathogenic players in disease pathogenesis (e.g., STMN2), as well as being able to modify disease progression (e.g., UNC13A). Thus, these aberrant splicing events make promising novel therapeutic targets to restore functional gene expression. Moreover, presence of these cryptic exons is highly specific to patients and areas of the brain affected by TDP-43 proteinopathy, offering the potential to develop biomarkers for early detection and stratification of patients. In summary, the discovery of cryptic exons gives hope for novel diagnostics and therapeutics on the horizon for TDP-43 proteinopathies.

Keywords: Amyotrophic lateral sclerosis; Biomarkers; Cryptic exons; Frontotemporal dementia; Motor neuron disease; STMN2; Splicing; TDP-43 proteinopathies; Therapeutics; UNC13A.

Fig. 1

Schematic summarising how cryptic exons (CEs) arise in the context of TDP-43 mislocalisation from the nucleus to the cytoplasm (owing to de-repression of splicing in intronic regions), possible downstream consequences (loss of functional protein, nonsense-mediated decay (NMD) of the cryptic-containing transcript, or translation of a novel cryptic peptide), and opportunities that CEs provide for better understanding disease mechanisms (STMN2, UNC13A, other genes yet to be explored), biomarker development (RNA and protein biomarkers), and therapeutics (via restoration of protein levels, or splicing modification)