The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

Authors

Alexander Bampton, The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.
Lauren M. Gittings, Department of Neurobiology, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.Follow
Pietro Fratta, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
Tammaryn Lashley, The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK. T.Lashley@ucl.ac.uk.
Ariana Gatt, The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.

Document Type

Article

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

Amyotrophic lateral sclerosis, Autoregulation, Frontotemporal dementia, RNA, hnRNP

Medical Subject Headings

Amyotrophic Lateral Sclerosis (metabolism, pathology); Animals; Frontotemporal Dementia (metabolism, pathology); Heterogeneous-Nuclear Ribonucleoproteins (metabolism); Humans

Publication Date

11-1-2020

Publication Title

Acta neuropathologica

E-ISSN

1432-0533

Volume

140

Issue

5

First Page

599

Last Page

623

PubMed ID

32748079

Digital Object Identifier (DOI)

10.1007/s00401-020-02203-0

Recommended Citation

Bampton, Alexander; Gittings, Lauren M.; Fratta, Pietro; Lashley, Tammaryn; and Gatt, Ariana, "The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis" (2020). Translational Neuroscience. 2314.
https://scholar.barrowneuro.org/neurobiology/2314