NUP62 — Nucleoporin 62

<table class="infobox infobox-gene">
<tr><th class="infobox-header" colspan="2">NUP62</th></tr>
<tr><td class="label">Full Name</td><td>Nucleoporin 62</td></tr>
<tr><td class="label">Chromosome</td><td>19q13.33</td></tr>
<tr><td class="label">NCBI Gene ID</td><td><a href="https://www.ncbi.nlm.nih.gov/gene/23636" target="_blank">23636</a></td></tr>
<tr><td class="label">Ensembl ID</td><td>ENSG00000213024</td></tr>
<tr><td class="label">OMIM ID</td><td>605815</td></tr>
<tr><td class="label">UniProt ID</td><td><a href="https://www.uniprot.org/uniprot/P37198" target="_blank">P37198</a></td></tr>
<tr><td class="label">Associated Diseases</td><td>[ALS](/diseases/als), [FTD](/diseases/ftd), [Huntington's Disease](/diseases/huntingtons-disease), Infantile Bilateral Striatal Necrosis</td></tr>
</table>

NUP62 — Nucleoporin 62

Overview

NUP62 encodes nucleoporin 62 (also known as p62), a critical component of the nuclear pore complex (NPC) central channel. As a phenylalanine-glycine (FG)-repeat nucleoporin, NUP62 forms the selective permeability barrier that controls bidirectional macromolecular transport between the nucleus and cytoplasm. NUP62 is essential for neuronal function and survival, and its dysfunction has been directly implicated in multiple neurodegenerative diseases, most prominently in [C9orf72](/genes/c9orf72)-associated [amyotrophic lateral sclerosis](/diseases/als) (ALS) and [frontotemporal dementia](/diseases/ftd) (FTD)[@chou2018].

<table class="infobox infobox-gene">
<tr><th class="infobox-header" colspan="2">NUP62</th></tr>
<tr><td class="label">Full Name</td><td>Nucleoporin 62</td></tr>
<tr><td class="label">Chromosome</td><td>19q13.33</td></tr>
<tr><td class="label">NCBI Gene ID</td><td><a href="https://www.ncbi.nlm.nih.gov/gene/23636" target="_blank">23636</a></td></tr>
<tr><td class="label">Ensembl ID</td><td>ENSG00000213024</td></tr>
<tr><td class="label">OMIM ID</td><td>605815</td></tr>
<tr><td class="label">UniProt ID</td><td><a href="https://www.uniprot.org/uniprot/P37198" target="_blank">P37198</a></td></tr>
<tr><td class="label">Associated Diseases</td><td>[ALS](/diseases/als), [FTD](/diseases/ftd), [Huntington's Disease](/diseases/huntingtons-disease), Infantile Bilateral Striatal Necrosis</td></tr>
</table>

NUP62 — Nucleoporin 62

Overview

NUP62 encodes nucleoporin 62 (also known as p62), a critical component of the nuclear pore complex (NPC) central channel. As a phenylalanine-glycine (FG)-repeat nucleoporin, NUP62 forms the selective permeability barrier that controls bidirectional macromolecular transport between the nucleus and cytoplasm. NUP62 is essential for neuronal function and survival, and its dysfunction has been directly implicated in multiple neurodegenerative diseases, most prominently in [C9orf72](/genes/c9orf72)-associated [amyotrophic lateral sclerosis](/diseases/als) (ALS) and [frontotemporal dementia](/diseases/ftd) (FTD)[@chou2018].

The NUP62 protein contains an N-terminal FG-repeat domain that creates a hydrogel-like meshwork within the central channel of the NPC, functioning as a selective filter that allows passive diffusion of small molecules while requiring active, [importin](/proteins/importin-beta-1)/exportin-mediated transport for larger cargo. Disruption of this barrier is increasingly recognized as a convergent pathological mechanism across multiple neurodegenerative diseases[@kim2017].

Gene Structure and Expression

NUP62 is located on chromosome 19q13.33 and spans approximately 22 kb of genomic DNA. The gene encodes a 522-amino acid protein with a molecular weight of approximately 62 kDa. The protein consists of three functional domains:

• N-terminal FG-repeat domain (residues 1-330): Contains approximately 20 FG-repeat motifs that form the NPC selective permeability barrier through hydrophobic interactions and phase separation
• Coiled-coil domain (residues 330-460): Mediates interactions with [NUP58](/genes/nup58) and [NUP54](/genes/nup54) within the central channel subcomplex
• C-terminal alpha-helical domain (residues 460-522): Anchors the NUP62 complex to the NPC scaffold

Function

Nuclear Pore Complex Assembly

NUP62 is part of the NUP62-NUP58-NUP54 central channel subcomplex. This trimeric complex forms the constriction ring of the NPC and is essential for:

• Selective permeability: Creating the FG-hydrogel that discriminates cargo by size and transport receptor binding
• NPC biogenesis: Required for de novo NPC assembly during interphase and post-mitotic NPC reconstitution
• NPC maintenance: Turnover and replacement of damaged nucleoporins in long-lived neurons

Nucleocytoplasmic Transport

NUP62 mediates the transport of critical neuronal cargo:

• Transcription factors: Nuclear import of [CREB](/genes/creb1), [NF-κB](/proteins/nf-kb), and [TFEB](/genes/tfeb)
• RNA export: mRNA export via the [NXF1](/genes/nxf1)-NXT1 pathway
• Protein quality control: Nuclear import of [ubiquitin](/proteins/ubiquitin) and proteasome components
• DNA repair factors: Import of [ATM](/genes/atm), [ATR](/genes/atr), and [BRCA1](/genes/brca1)

Neuronal-Specific Functions

In neurons, NUP62 plays specialized roles beyond general transport:

• Synaptic plasticity: Regulating nuclear import of activity-dependent transcription factors during [long-term potentiation](/mechanisms/synaptic-plasticity)
• Axonal maintenance: NPC integrity in long axons depends on stable NUP62 incorporation
• Calcium signaling: NPC gating is calcium-sensitive, and NUP62 contributes to calcium-dependent nuclear import regulation

Disease Associations

C9orf72-ALS/FTD — Nuclear Transport Collapse

The most significant neurodegenerative disease connection for NUP62 involves [C9orf72](/genes/c9orf72) repeat expansion-associated ALS and FTD. The GGGGCC hexanucleotide repeat expansion in [C9orf72](/entities/c9orf72) produces toxic dipeptide repeat (DPR) proteins through repeat-associated non-ATG (RAN) translation. Two arginine-containing DPRs — poly(GR) and poly(PR) — directly disrupt NPC function by interacting with NUP62[@freibaum2015]:

• Poly(PR) binds NUP62 FG-repeats: Poly(PR) peptides phase-separate with the FG-repeat domain of NUP62, disrupting the selective permeability barrier. This was demonstrated through in vitro reconstitution showing that poly(PR) alters the biophysical properties of the NUP62 FG-hydrogel[@shi2017]
• Poly(GA) sequesters NUP62: Poly(GA) aggregates recruit NUP62 into cytoplasmic inclusions, depleting functional nucleoporins from the NPC[@gassetrosa2017]
• [TDP-43](/genes/tardbp) nuclear clearance: NUP62 dysfunction impairs nuclear import of [TDP-43](/proteins/tdp-43-protein), driving its cytoplasmic mislocalization and aggregation — a hallmark of ALS/FTD pathology
• RNA export block: NUP62 disruption impairs bulk mRNA export, contributing to nuclear RNA foci formation

Huntington's Disease

NUP62 is disrupted in [Huntington's disease](/diseases/huntington-disease) through mutant [huntingtin](/proteins/huntingtin-protein) (mHTT) interactions:

• mHTT sequestration: Mutant [huntingtin](/proteins/huntingtin) with expanded polyglutamine tracts sequesters NUP62 and other nucleoporins into cytoplasmic aggregates
• Nuclear transport deficits: Impaired import of [CREB](/genes/creb1) and other transcription factors contributes to transcriptional dysregulation
• Age-dependent decline: NPC deterioration in HD striatal neurons correlates with disease progression[@grima2017]

Infantile Bilateral Striatal Necrosis (IBSN)

Biallelic loss-of-function mutations in NUP62 cause infantile bilateral striatal necrosis, a devastating early-onset neurodegenerative disease characterized by:

• Progressive dystonia and choreoathetosis
• Bilateral striatal degeneration on MRI
• Developmental regression
• This Mendelian disorder demonstrates the essential requirement of NUP62 for striatal neuron survival[@baselvanagaite2006]

Aging-Related Neurodegeneration

Even in the absence of specific disease mutations, age-related deterioration of NUP62 contributes to neuronal vulnerability:

• Oxidative damage: FG-repeats are susceptible to oxidative modification, which disrupts the permeability barrier
• Carbonylation: NUP62 carbonylation increases with age in post-mitotic neurons, impairing NPC function
• Reduced turnover: Unlike dividing cells that replenish NPCs during mitosis, neurons must maintain the same NPCs for decades
• Nuclear leakiness: Age-dependent NPC deterioration causes progressive nuclear envelope permeability, allowing aberrant cytoplasmic-nuclear mixing[@dangelo2009]

Therapeutic Implications

Nuclear Transport Restoration

NUP62 biology has inspired several therapeutic strategies:

• Nucleoporin overexpression: Viral delivery of NUP62 or related nucleoporins to restore NPC function in C9orf72-ALS models
• Nuclear export inhibitors: [KPT-350](/therapeutics/kpt-350) (selinexor analogs) that partially compensate for import deficits by reducing export
• DPR-targeting ASOs: Antisense oligonucleotides targeting C9orf72 repeat transcripts to prevent DPR-mediated NUP62 disruption
• Small molecules: Compounds that stabilize the FG-hydrogel against DPR disruption

Biomarker Potential

• Soluble NUP62 fragments in cerebrospinal fluid may serve as biomarkers of NPC integrity
• NPC morphology assessable via super-resolution microscopy of patient-derived neurons

Key Research Findings

• D'Angelo et al. (2009) demonstrated that NPC deterioration is a feature of aging in post-mitotic cells, with NUP62 among the most affected nucleoporins[@dangelo2009]
• Freibaum et al. (2015) showed that C9orf72 DPRs disrupt nuclear transport through direct interaction with NUP62 and other FG-nucleoporins[@freibaum2015]
• Gasset-Rosa et al. (2017) demonstrated NUP62 mislocalization in C9orf72-ALS patient motor neurons and iPSC-derived neurons[@gassetrosa2017]
• Grima et al. (2017) identified nuclear pore pathology in Huntington's disease and showed NUP62 sequestration by mutant huntingtin[@grima2017]

See Also

• [C9orf72](/genes/c9orf72) — Hexanucleotide repeat expansion causing ALS/FTD
• [NUP98](/genes/nup98) — Another key FG-nucleoporin disrupted in neurodegeneration
• [TDP-43](/genes/tardbp) — RNA-binding protein whose nuclear clearance depends on NPC integrity
• [Nuclear Transport Defects in Neurodegeneration](/mechanisms/nuclear-transport-defects)
• [Amyotrophic Lateral Sclerosis](/diseases/als)
• [Frontotemporal Dementia](/diseases/ftd)

External Links

• [NCBI Gene: NUP62](https://www.ncbi.nlm.nih.gov/gene/23636)
• [UniProt: P37198](https://www.uniprot.org/uniprot/P37198)
• [GeneCards: NUP62](https://www.genecards.org/cgi-bin/carddisp.pl?gene=NUP62)
• [OMIM: 605815](https://omim.org/entry/605815)
• [Allen Brain Atlas: NUP62](https://portal.brain-map.org/explore/genes?searchType=gene&query=NUP62)

References