NUP62 (Nucleoporin 62, p62) is a critical component of the nuclear pore complex (NPC) central transport channel, where it forms the NUP62 sub-complex together with [NUP54](/proteins/nup54-protein) and [NUP58](/proteins/nup58-protein).[@chug2015][@grandi1997] Through its phenylalanine-glycine (FG) repeat domain, NUP62 creates a selective permeability barrier that governs nucleocytoplasmic transport of proteins and RNA — a process increasingly recognized as fundamentally disrupted in neurodegenerative diseases including [ALS](/diseases/als), [FTD](/diseases/ftd), and [Alzheimer's disease](/diseases/alzheimers-disease).[@kim2017][@freibaum2015]
NUP62 (Nucleoporin 62, p62) is a critical component of the nuclear pore complex (NPC) central transport channel, where it forms the NUP62 sub-complex together with [NUP54](/proteins/nup54-protein) and [NUP58](/proteins/nup58-protein).[@chug2015][@grandi1997] Through its phenylalanine-glycine (FG) repeat domain, NUP62 creates a selective permeability barrier that governs nucleocytoplasmic transport of proteins and RNA — a process increasingly recognized as fundamentally disrupted in neurodegenerative diseases including [ALS](/diseases/als), [FTD](/diseases/ftd), and [Alzheimer's disease](/diseases/alzheimers-disease).[@kim2017][@freibaum2015]
Structure
NUP62 contains an N-terminal FG-repeat domain (~200 residues) that is intrinsically disordered and forms the hydrogel-like meshwork within the NPC central channel.[@chug2015][@schmidt2015] The C-terminal coiled-coil domain mediates trimerization with NUP54 and NUP58 to anchor the complex within the NPC scaffold.[@grandi1997] O-linked N-acetylglucosamine (O-GlcNAc) modification of the FG-repeat domain dynamically regulates pore permeability and transport selectivity.[@zhu2016] The FG-repeat domain can undergo liquid-liquid phase separation (LLPS), forming hydrogel-like condensates that recapitulate the NPC selectivity barrier in vitro.[@schmidt2015]
Normal Function
In healthy [neurons](/entities/neurons), NUP62 performs several essential functions:
Nucleocytoplasmic transport gating: The FG-repeat meshwork creates a size-selective barrier (~40 kDa cutoff for passive diffusion) while permitting importin/exportin-mediated active transport of cargo proteins and mRNA.[@chug2015][@kim2017]
mRNA export quality control: NUP62 participates in the TREX-2/GANP pathway that ensures properly processed mRNAs are exported, while aberrant transcripts are retained for degradation.[@wickramasinghe2010]
Gene expression regulation: NUP62 can associate with chromatin at gene promoters, acting as a transcriptional co-regulator independent of its transport function — particularly at developmental and activity-responsive loci in neurons.[@ibarra2016]
Cell cycle and DNA repair: Through interactions with the SUMO pathway and DNA damage response machinery, NUP62 coordinates nuclear envelope integrity with genome maintenance.[@lemaitre2011]
Role in Neurodegeneration
Nucleocytoplasmic transport dysfunction mediated by NUP62 degradation is emerging as a convergent pathomechanism across multiple neurodegenerative diseases:
ALS/FTD
[C9orf72](/genes/c9orf72) hexanucleotide repeat expansions — the most common genetic cause of ALS/FTD — produce dipeptide repeat proteins (DPRs) that directly bind and disrupt NUP62 FG-repeat hydrogels, collapsing the NPC selectivity barrier.[@freibaum2015][@shi2017] Poly-glycine-alanine (poly-GA) and poly-proline-arginine (poly-PR) DPRs show particular affinity for NUP62, displacing transport receptors and causing cytoplasmic mislocalization of nuclear proteins including [TDP-43](/proteins/tdp-43).[@zhang2015] [TDP-43](/mechanisms/tdp-43-proteinopathy) mislocalization itself further damages NPCs by sequestering NUP62 mRNA, creating a self-amplifying destructive cycle.[@chou2018]
Alzheimer's Disease
[Tau](/proteins/tau) pathology disrupts NPC integrity through direct interaction with NUP62. Hyperphosphorylated [tau](/proteins/tau) binds the NUP62 FG domain, impairing nuclear import of transcription factors essential for neuronal survival.[@eftekharzadeh2018] In human AD brain tissue, NUP62 levels are reduced by 30-50% in neurons bearing neurofibrillary tangles, correlating with impaired Ran-GTPase gradient maintenance.[@sheffield2006] [Amyloid-beta](/proteins/amyloid-beta) oligomers also indirectly deplete NUP62 through oxidative modification of the O-GlcNAc cycling machinery.[@zhu2016]
Aging
Age-dependent oxidative damage to long-lived NUP62 protein (NPC components are among the most stable proteins in neurons, with half-lives exceeding years) progressively degrades transport fidelity, potentially establishing a vulnerability threshold for neurodegeneration.[@dangelo2009][@toyama2013]
Therapeutic Targeting
Strategies to restore NUP62 function and nucleocytoplasmic transport integrity include:
Nuclear transport modifiers: Small molecules that stabilize NUP62 FG-repeat phase separation properties, preventing DPR-mediated disruption.[@shi2017]
Importin/exportin enhancers: Compounds like KPT-350 (selective inhibitor of nuclear export via XPO1) that rebalance transport flux when NPC function is compromised.[@haines2015]
O-GlcNAc modulators: OGA inhibitors (e.g., thiamet-G) that increase NUP62 O-GlcNAcylation, potentially protecting FG-repeat domain integrity under proteotoxic stress.[@zhu2016]
Antisense oligonucleotides: ASOs targeting [C9orf72](/entities/c9orf72) repeat RNA to prevent DPR production and downstream NUP62 disruption.[@zhang2015]
See Also
[NUP62](/genes/nup62)
[NUP98 Protein](/proteins/nup98-protein)
[C9orf72](/genes/c9orf72)
[TDP-43](/proteins/tdp-43)
[Nucleocytoplasmic Transport Defects](/mechanisms/nucleocytoplasmic-transport-defects)
[Chug H, Trakhanov S, Hülsmann BB, et al, Crystal structure of the metazoan Nup62-Nup58-Nup54 nucleoporin complex (2015)](https://doi.org/10.1126/science.aab2386)
[Grandi P, Dang T, Pané N, et al, Nup93 is a component of the nuclear pore complex connecting the inner basket with the central channel (1997)](https://doi.org/10.1083/jcb.126.3.603)
[Kim HJ, Taylor JP, Lost in transportation: nucleocytoplasmic transport deficits in ALS and other neurodegenerative diseases (2017)](https://doi.org/10.1016/j.neuron.2017.07.029)
[Freibaum BD, Lu Y, Lopez-Gonzalez R, et al, GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport (2015)](https://doi.org/10.1038/nature15723)
[Schmidt HB, Görlich D, Nup98 FG domains from diverse species spontaneously phase-separate into particles with nuclear pore-like permselectivity (2015)](https://doi.org/10.7554/eLife.04251)
[Zhu Y, Liu TW, Madden Z, et al, Post-translational O-GlcNAcylation is essential for nuclear pore integrity and maintenance of the pore selectivity filter (2016)](https://doi.org/10.1074/jbc.M115.673525)
[Wickramasinghe VO, McMurtrie PI, Mills AD, et al, mRNA export from mammalian cell nuclei is dependent on GANP (2010)](https://doi.org/10.1016/j.cub.2010.01.011)
[Ibarra A, Benner C, Tyber A, Hetzer MW, Nucleoporin-mediated regulation of cell identity genes (2016)](https://doi.org/10.1101/gad.268763.115)
[Lemaitre C, Fischer B, Kalousi A, et al, The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response (2011)](https://doi.org/10.1038/onc.2011.519)
[Shi KY, Mack E, Bhatt DL, et al, Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export (2017)](https://doi.org/10.1073/pnas.1620293114)
[Zhang K, Donnelly CJ, Haeusler AR, et al, The C9orf72 repeat expansion disrupts nucleocytoplasmic transport (2015)](https://doi.org/10.1038/nature15723)
[Chou CC, Zhang Y, Bhatt DL, et al, TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD (2018)](https://doi.org/10.1038/s41593-018-0175-2)
[Eftekharzadeh B, Daiber JA, Bhatt DL, et al, Tau protein disrupts nucleocytoplasmic transport in Alzheimer's disease (2018)](https://doi.org/10.1016/j.neuron.2018.07.039)
[D'Angelo MA, Raices M, Bhatt DL, et al, Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells (2009)](https://doi.org/10.1016/j.cell.2009.01.019)
[Toyama BH, Savas JN, Park SK, et al, Identification of long-lived proteins reveals exceptional stability of histones and nuclear pore complexes (2013)](https://doi.org/10.1016/j.cell.2013.07.037)
[Haines JD, Herbin O, de la Hera B, et al, Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination (2015)](https://doi.org/10.1038/nn.4033)