Journal Article

The era of cryptic exons: implications for ALS-FTD

Ward, Michael E., Mehta, Puja R., Brown, Anna-Leigh, Fratta, Pietro

2023

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Alzheimer's disease / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - metabolism / Binding sites / Biomarkers / Biomedical and Life Sciences / Biomedicine / Cryptic exons / Cytoplasm / Dementia disorders / Development and progression / Exons / Exons - genetics / Frontotemporal dementia / Frontotemporal Dementia - metabolism / Gene expression / Genes / Health risk assessment / Humans / Molecular Medicine / Motor neuron disease / Mutation / Nervous system diseases / Neurodegeneration / Neurodegenerative diseases / Neurodegenerative Diseases - metabolism / Neurology / Neurons / Neurons - metabolism / Neurosciences / Pathogenesis / Pathology / Patients / Protein binding / Proteins / Review / RNA / RNA-binding protein / Splicing / TDP-43 proteinopathies / TDP-43 Proteinopathies - metabolism / Therapeutic targets