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The coming-of-age of nucleocytoplasmic transport in motor neuron disease and neurodegeneration

  • Paulo A. FerreiraEmail author
Review
  • 193 Downloads

Abstract

The nuclear pore is the gatekeeper of nucleocytoplasmic transport and signaling through which a vast flux of information is continuously exchanged between the nuclear and cytoplasmic compartments to maintain cellular homeostasis. A unifying and organizing principle has recently emerged that cements the notion that several forms of amyotrophic lateral sclerosis (ALS), and growing number of other neurodegenerative diseases, co-opt the dysregulation of nucleocytoplasmic transport and that this impairment is a pathogenic driver of neurodegeneration. The understanding of shared pathomechanisms that underpin neurodegenerative diseases with impairments in nucleocytoplasmic transport and how these interface with current concepts of nucleocytoplasmic transport is bound to illuminate this fundamental biological process in a yet more physiological context. Here, I summarize unresolved questions and evidence and extend basic and critical concepts and challenges of nucleocytoplasmic transport and its role in the pathogenesis of neurodegenerative diseases, such as ALS. These principles will help to appreciate the roles of nucleocytoplasmic transport in the pathogenesis of ALS and other neurodegenerative diseases, and generate a framework for new ideas of the susceptibility of motoneurons, and possibly other neurons, to degeneration by dysregulation of nucleocytoplasmic transport.

Keywords

Neurodegeneration Nucleocytoplasmic transport Amyotrophic lateral sclerosis (ALS) Motor neurons Ran GTPase Ran-binding protein 2 (Ranbp2) Exportin-1/CRM1 Importin Karyopherin Nucleoporin 

Abbreviations

ALS

Amyotrophic lateral sclerosis

Ranbp2

Ran-binding protein 2

Ranbp1

Ran-binding protein 1

RBDs

Ran-GTP-binding domains

ZnF

Zinc-finger motif

Nup

Nucleoporin

CY

Cyclophilin

RCC1

Regulator of chromosome condensation 1

RanGAP1

Ran GTPase-activating protein-1

NTRs

Nuclear transport receptors

NES

Nuclear export sequence

NLS

Nuclear localization sequence

mRNP

Messenger ribonucleoprotein

TREX

Transcription–export complex,

hnRNPs

Heterogeneous nuclear ribonucleoproteins

CBC

Cap-binding complex

EJC

Exon-junction complex

eIF

Eukaryotic initiation factor

SRP

Signal recognition particle

SSCR

Signal sequence-coding region

ALREX

Alternative mRNA nuclear export

Cxcl14

Chemokine ligand 14

Acc1

Acetyl-CoA carboxylase 1

SOD1

Cu/Zn Superoxide dismutase 1,

C9ORF72

Chromosome 9 Open Reading Frame 72

TARDBP

Transactive response DNA-binding protein (TDP-43)

FUS

Fused in sarcoma

DPRs

Dipeptide repeat proteins

LCCS1

Lethal congenital contracture syndrome 1

LAAHD

Lethal arthrogryposis with anterior horn cell disease

Ran

Ras-related nuclear protein

Notes

Funding

This work was in part funded by National Institutes of Health Grants GM083165, GM083165-03S1 and EY019492 to P.A.F.

Compliance with ethical standards

Conflict of interest

The author declares no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author consents for the publication of this study.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Duke University Medical CenterDurhamUSA

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