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

  • Paulo A. FerreiraEmail author


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.


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



Amyotrophic lateral sclerosis


Ran-binding protein 2


Ran-binding protein 1


Ran-GTP-binding domains


Zinc-finger motif






Regulator of chromosome condensation 1


Ran GTPase-activating protein-1


Nuclear transport receptors


Nuclear export sequence


Nuclear localization sequence


Messenger ribonucleoprotein


Transcription–export complex,


Heterogeneous nuclear ribonucleoproteins


Cap-binding complex


Exon-junction complex


Eukaryotic initiation factor


Signal recognition particle


Signal sequence-coding region


Alternative mRNA nuclear export


Chemokine ligand 14


Acetyl-CoA carboxylase 1


Cu/Zn Superoxide dismutase 1,


Chromosome 9 Open Reading Frame 72


Transactive response DNA-binding protein (TDP-43)


Fused in sarcoma


Dipeptide repeat proteins


Lethal congenital contracture syndrome 1


Lethal arthrogryposis with anterior horn cell disease


Ras-related nuclear protein



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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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Duke University Medical CenterDurhamUSA

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