The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis
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REVIEW
The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis Alexander Bampton1,2 · Lauren M. Gittings3 · Pietro Fratta4 · Tammaryn Lashley1,2 · Ariana Gatt1,2 Received: 25 June 2020 / Revised: 27 July 2020 / Accepted: 27 July 2020 © The Author(s) 2020
Abstract Dysregulated RNA metabolism is emerging as a crucially important mechanism underpinning the pathogenesis of frontotemporal dementia (FTD) and the clinically, genetically and pathologically overlapping disorder of amyotrophic lateral sclerosis (ALS). Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins with diverse, multi-functional roles across all aspects of mRNA processing. The role of these proteins in neurodegeneration is far from understood. Here, we review some of the unifying mechanisms by which hnRNPs have been directly or indirectly linked with FTD/ALS pathogenesis, including their incorporation into pathological inclusions and their best-known roles in pre-mRNA splicing regulation. We also discuss the broader functionalities of hnRNPs including their roles in cryptic exon repression, stress granule assembly and in co-ordinating the DNA damage response, which are all emerging pathogenic themes in both diseases. We then present an integrated model that depicts how a broad-ranging network of pathogenic events can arise from declining levels of functional hnRNPs that are inadequately compensated for by autoregulatory means. Finally, we provide a comprehensive overview of the most functionally relevant cellular roles, in the context of FTD/ALS pathogenesis, for hnRNPs A1-U. Keywords hnRNP · Frontotemporal dementia · Amyotrophic lateral sclerosis · RNA · Autoregulation
Introduction Frontotemporal lobar degeneration (FTLD) is an umbrella pathological term that encompasses a group of heterogeneous neurodegenerative disorders known to cause frontotemporal dementia (FTD) [108]. FTLD is believed to lie on a single disease continuum with the neuromuscular disease amyotrophic lateral sclerosis (ALS) [52]. Indeed, disrupted Tammaryn Lashley and Ariana Gatt: Joint senior authors. * Tammaryn Lashley [email protected] 1
The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK
2
Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK
3
Department of Neurobiology, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA
4
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
RNA and protein homeostasis have been identified as converging mechanisms of neurotoxicity in both disorders. RNA-binding proteins (RBPs) play a central role in regulating all aspects of gene expression, hence their dysfunction is likely to be a key contributing feature of disrupted RNA and protein homeostasis in these diseases [118]. The heterogeneous nuclear ribonucleoprotein (hnRNP) family is a family of RBPs containi
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