Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration

Abstract

Nucleocytoplasmic transport (NCT) across the nuclear envelope is precisely regulated in eukaryotic cells, and it plays critical roles in maintenance of cellular homeostasis. Accumulating evidence has demonstrated that dysregulations of NCT are implicated in aging and age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and Huntington disease (HD). This is an emerging research field. The molecular mechanisms underlying impaired NCT and the pathogenesis leading to neurodegeneration are not clear. In this review, we comprehensively described the components of NCT machinery, including nuclear envelope (NE), nuclear pore complex (NPC), importins and exportins, RanGTPase and its regulators, and the regulatory mechanisms of nuclear transport of both protein and transcript cargos. Additionally, we discussed the possible molecular mechanisms of impaired NCT underlying aging and neurodegenerative diseases, such as ALS/FTD, HD, and AD.

A Recurrent KPNA3 Missense Variant Causing Infantile Pure Spastic Paraplegia

“…In AQP4 IgG-positive NMOSD, complement activation correlates with disease severity. 4,5 In contrast, MOGAD lesions are often reversible and, in this study, the levels of complement proteins do not correlate with presentation or presumed severity. • It is increasingly recognized that many patients with MOGAD have viral infection or vaccination prior to attack.…”

“…Nucleocytoplasmic transport is an emerging research area in neurodegenerative diseases (eg, amyotrophic lateral sclerosis [ALS] and Huntington's disease 4 ) although the connection with HSP was not very well established prior to the recent report of Schob et al 1 Although the authors show a diminished expression of several KPNA3 variants in HEK293T cells, this is not the case for the p.Thr315Ile mutation. Furthermore, impaired endogenous cargo binding is only shown for 2 of the 4 tested partners, whereas other mutations affect all 4 partners.…”

KPNB1 modulates the Machado–Joseph disease protein ataxin-3 through activation of the mitochondrial protease CLPP

“…The appropriate subcellular localization of proteins is essential for their physiological functions and the maintenance of cellular homeostasis [ 52 ]. In recent years, there has been a growing appreciation for the idea that dysregulation of the nucleocytoplasmic transport machinery plays a critical role in the pathogenesis of various neurodegenerative diseases.…”

Characterizing Binding Interactions That Are Essential for Selective Transport through the Nuclear Pore Complex

“…Unsurprisingly, errors in selective transport can lead to cellular dysregulation. Aberrant nucleocytoplasmic transport has been implicated in aging, neurodegenerative disorders (e.g., amyotrophic lateral sclerosis, Alzheimer’s disease, frontotemporal dementia, Huntington’s disease, Parkinson’s disease), viral infections, autoimmune disorders, and cancer [ 24 , 25 , 26 , 27 ]. In pathological conditions, Nups and/or NPC associated proteins can have missense mutations [ 28 ], protein alterations (e.g., truncation, fusion) [ 29 , 30 ], and anomalous expressions [ 31 , 32 ].…”