Heterogeneous Nuclear Ribonucleoproteins: Implications in Neurological Diseases
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Heterogeneous Nuclear Ribonucleoproteins: Implications in Neurological Diseases Yi-Hua Low 1,2 & Yasmine Asi 1 & Sandrine C. Foti 1,3 & Tammaryn Lashley 1,3 Received: 29 June 2020 / Accepted: 17 September 2020 # The Author(s) 2020
Abstract Heterogenous nuclear ribonucleoproteins (hnRNPs) are a complex and functionally diverse family of RNA binding proteins with multifarious roles. They are involved, directly or indirectly, in alternative splicing, transcriptional and translational regulation, stress granule formation, cell cycle regulation, and axonal transport. It is unsurprising, given their heavy involvement in maintaining functional integrity of the cell, that their dysfunction has neurological implications. However, compared to their more established roles in cancer, the evidence of hnRNP implication in neurological diseases is still in its infancy. This review aims to consolidate the evidences for hnRNP involvement in neurological diseases, with a focus on spinal muscular atrophy (SMA), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), congenital myasthenic syndrome (CMS), and fragile X-associated tremor/ataxia syndrome (FXTAS). Understanding more about hnRNP involvement in neurological diseases can further elucidate the pathomechanisms involved in these diseases and perhaps guide future therapeutic advances. Keywords hnRNPs . Alzheimer’s disease . Multiple sclerosis . ALS . FTD
Introduction Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a family of functionally diverse RNA bindings proteins (RBPs) [1]. Originally named alphabetically from A1 to U, they range from 34 to 120 kDA [2]. Their high involvement in RNA metabolic processes including pre-mRNA processing, splicing, and nucleocytoplasmic shuttling makes them pivotal in the regulation of gene expression [3]. Having a substantial control over post-transcriptional modifications and translation, it is unsurprising that aberrance in hnRNP function can lead to dire functional consequences. While their role in regulating several cellular processes is established, their role in neurological diseases has not been comprehensively investigated. This review aims to consolidate the existing literature
* Tammaryn Lashley [email protected] 1
The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Disorders, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
2
Duke-NUS Medical School, Singapore, Singapore
3
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK
of hnRNP abnormalities in various neurological diseases and spur further research in this area.
Structure of hnRNPs Four evolutionary conserved RNA binding domains (RBD) have been elucidated in hnRNPs. The RNA recognition motif (RRM) is one of the most abundant protein domains in eukaryotes and was first discovered in the U1A protein [4]. It consists of 4 β-sheet (β4β1β3β2) and 2 α-helix (α
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