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

• Published in: Cellular and molecular life sciences : CMLS Vol. 76; no. 12; pp. 2247 - 2273
• Main Author: Ferreira, Paulo A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-06-2019; Springer Nature B.V
• Subjects: Active Transport, Cell Nucleus; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Axonal transport; Biochemistry; Biological activity; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Nucleus - metabolism; Cell Nucleus - pathology; Cytoplasm - metabolism; Cytoplasm - pathology; Degeneration; Homeostasis; Humans; Life Sciences; Motor Neuron Disease - metabolism; Motor Neuron Disease - pathology; Motor neuron diseases; Motor neurone disease; Motor neurons; Motor Neurons - metabolism; Motor Neurons - pathology; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurological diseases; Pathogenesis; Review; Transport; Motor neurons; Ran-binding protein 2 (Ranbp2); Exportin-1/CRM1; Neurodegeneration; Amyotrophic lateral sclerosis (ALS); Importin; Nucleocytoplasmic transport; Ran GTPase; Karyopherin; Nucleoporin
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-019-03029-0

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.