<table class="infobox infobox-gene">
<tr><th class="infobox-header" colspan="2">NUP98</th></tr>
<tr><td class="label">Full Name</td><td>Nucleoporin 98</td></tr>
<tr><td class="label">Chromosome</td><td>11p15.4</td></tr>
<tr><td class="label">NCBI Gene ID</td><td><a href="https://www.ncbi.nlm.nih.gov/gene/4928" target="_blank">4928</a></td></tr>
<tr><td class="label">Ensembl ID</td><td>ENSG00000110713</td></tr>
<tr><td class="label">OMIM ID</td><td>601021</td></tr>
<tr><td class="label">UniProt ID</td><td><a href="https://www.uniprot.org/uniprot/P52948" target="_blank">P52948</a></td></tr>
<tr><td class="label">Associated Diseases</td><td>[ALS](/diseases/als), [FTD](/diseases/ftd), [Alzheimer's Disease](/diseases/alzheimers-disease), [Huntington's Disease](/diseases/huntingtons-disease)</td></tr>
</table>
NUP98 — Nucleoporin 98
Overview
Mermaid diagram (expand to render)
NUP98 encodes nucleoporin 98, one of the most abundant phenylalanine-glycine (FG)-repeat nucleoporins in the nuclear pore complex (NPC). NUP98 plays a dual role as both a structural component of the NPC permeability barrier and a mobile transcriptional regulator that shuttles between the NPC and the nucleoplasm. Its extensive FG-repeat domain — the largest of any nucleoporin — forms the primary selective filter controlling nucleocytoplasmic transport. NUP98 dysfunction has emerged as a convergent pathological node in multiple neurodegenerative diseases, including [C9orf72](/genes/c9orf72)-ALS/FTD, [Alzheimer's disease](/diseases/alzheimers-disease), and [Huntington's disease](/diseases/huntington-disease)[@jovii2015].
Unlike most nucleoporins, NUP98 is not permanently embedded in the NPC. It dynamically associates with nuclear pores and also functions in the nucleoplasm, where it regulates gene expression through interaction with chromatin. This dual localization makes NUP98 uniquely positioned to couple transport competence with transcriptional programs — and uniquely vulnerable to disruption in aging and disease["@kalverda2010"].
Gene Structure and Expression
NUP98 is located on chromosome 11p15.4 and spans approximately 120 kb. The gene produces multiple transcripts through alternative splicing, with the primary isoform encoding an 1817-amino acid protein. A critical post-translational event is autoproteolytic cleavage, which generates two functional fragments:
- NUP98-N (residues 1-863): Contains the GLFG-repeat domain (approximately 40 FG-repeats), a Gle2-binding sequence (GLEBS domain), and functions as the NPC permeability barrier component
- NUP98-C (residues 864-1817): Contains the Nup96 protein, an essential scaffold nucleoporin with a beta-propeller domain that anchors the Y-complex to the NPC
NUP98 is highly expressed in [neurons](/entities/neurons) throughout the central nervous system, with enrichment in the [hippocampus](/brain-regions/hippocampus), [prefrontal cortex](/brain-regions/prefrontal-cortex), [motor cortex](/brain-regions/motor-cortex), and [cerebellum](/brain-regions/cerebellum). In post-mitotic neurons, NUP98 has a remarkably long half-life, with proteomic studies demonstrating persistence for months to years — making it one of the longest-lived proteins in the nervous system[@toyama2013].
Function
Nuclear Pore Permeability Barrier
NUP98 is the principal architect of the NPC selective barrier:
- FG-hydrogel formation: The GLFG-repeat domain self-assembles into a cohesive hydrogel that fills the central channel, excluding macromolecules larger than ~40 kDa unless chaperoned by transport receptors
- Transport selectivity: [Importin-beta](/proteins/importin-beta-1) and exportins transiently dissolve local FG-repeat interactions, allowing cargo to traverse the barrier
- Barrier regeneration: After each transport event, the FG-hydrogel spontaneously re-seals
- Central vs. peripheral localization: NUP98 contributes to both the central channel barrier and cytoplasmic filament-associated gating
Transcriptional Regulation
Beyond its NPC structural role, NUP98 functions as a transcriptional regulator:
- Gene activation at NPCs: NUP98 tethers actively transcribed genes to the nuclear periphery, facilitating co-transcriptional mRNA export
- Chromatin remodeling: NUP98-N interacts with the [CREB-binding protein (CBP/p300)](/genes/ep300) acetyltransferase and the [SET domain](/proteins/setd2-protein) methyltransferase complex
- Epigenetic memory: NUP98 maintains transcriptional memory of recently active genes during cell division
- Developmental gene regulation: NUP98 regulates [Hox gene](/genes/hoxa1) clusters and other developmental programs critical for neuronal differentiation
mRNA Export and Processing
NUP98 is essential for mRNA export:
- mRNA surveillance: The GLEBS domain recruits Rae1/Gle2 to couple mRNA quality control with export competence
- Bulk mRNA export: NUP98 facilitates the [NXF1](/genes/nxf1)-mediated mRNA export pathway
- Selective export: Certain mRNA species, including neuronal activity-dependent transcripts, preferentially require NUP98 for export
Disease Associations
NUP98 is a primary target of dipeptide repeat (DPR) protein toxicity in [C9orf72](/genes/c9orf72)-associated ALS/FTD:
- Poly(PR) disruption: Arginine-rich DPRs (poly-PR, poly-GR) phase-separate with NUP98 FG-repeats, converting the functional hydrogel into aberrant solid-like aggregates that obstruct transport[@shi2017]
- In vitro reconstitution: Purified NUP98 FG-hydrogels mixed with poly(PR) peptides show complete loss of selective permeability — transport receptors can no longer dissolve the barrier
- NUP98 redistribution: In [C9orf72](/entities/c9orf72)-ALS patient motor neurons, NUP98 is depleted from NPCs and accumulates in cytoplasmic puncta co-localizing with DPR inclusions[@zhang2015]
- [TDP-43](/genes/tardbp) mislocalization: NUP98 dysfunction is a proximal cause of [TDP-43](/proteins/tdp-43-protein) nuclear clearance, the pathological hallmark of ALS/FTD
- mRNA export failure: Loss of NUP98-mediated mRNA export contributes to nuclear RNA foci, a characteristic feature of C9orf72 disease
Genetic rescue experiments demonstrate that overexpression of NUP98 or related nucleoporins suppresses DPR toxicity in
Drosophila and iPSC-derived motor neuron models[@freibaum2015].
Alzheimer's Disease
NUP98 is implicated in [Alzheimer's disease](/diseases/alzheimers-disease) pathogenesis through multiple mechanisms:
- [Tau](/genes/mapt)-mediated NPC disruption: Hyperphosphorylated [tau](/proteins/tau) directly interacts with NUP98, disrupting the NPC permeability barrier. This was demonstrated in Drosophila tauopathy models where tau overexpression caused NUP98 mislocalization and nuclear lamin invaginations[@eftekharzadeh2018]
- NPC deterioration in aging neurons: Age-dependent oxidative damage to NUP98 FG-repeats compromises NPC integrity in hippocampal neurons, potentially contributing to the earliest stages of AD pathogenesis
- [Amyloid-beta](/proteins/amyloid-beta) effects: Aβ oligomers induce calcium dysregulation that alters NPC permeability and NUP98 dynamics
- Transcriptional dysregulation: Loss of NUP98-mediated gene tethering disrupts expression of neuroprotective genes
Huntington's Disease
In [Huntington's disease](/diseases/huntington-disease), mutant [huntingtin](/proteins/huntingtin-protein) disrupts NUP98 function:
- Polyglutamine sequestration: Expanded polyglutamine tracts in mutant [huntingtin](/proteins/huntingtin) interact with and sequester NUP98 into cytoplasmic inclusions
- Striatal vulnerability: NUP98 mislocalization is particularly pronounced in medium spiny neurons of the [striatum](/brain-regions/striatum), correlating with their selective vulnerability in HD
- [RanGAP1](/proteins/rangap1) co-disruption: NUP98 displacement co-occurs with mislocalization of RanGAP1, further degrading the Ran-GTP gradient essential for directional transport[@grima2017]
Aging-Associated Nuclear Transport Decline
NUP98 is central to the age-dependent decline in nuclear transport:
- Extreme longevity: NUP98 protein in neurons can persist for the organism's entire lifespan, accumulating oxidative damage over decades
- Carbonylation: Progressive carbonylation of NUP98 FG-repeats disrupts hydrogel cohesion
- Leaky nuclei: NUP98 deterioration causes increasing nuclear envelope permeability in aging neurons, allowing aberrant mixing of nuclear and cytoplasmic contents[@dangelo2009]
- Senescence nexus: NUP98 damage may trigger cellular senescence pathways, connecting nuclear transport decline to [neuroinflammation](/mechanisms/neuroinflammation)
Therapeutic Implications
Strategies Targeting NUP98 Dysfunction
- NUP98 gene therapy: AAV-mediated delivery of NUP98 to restore NPC function in C9orf72-ALS models
- DPR clearance: Approaches targeting DPR production (antisense oligonucleotides against C9orf72 repeats) or clearance ([autophagy](/entities/autophagy) induction) to prevent NUP98 disruption
- FG-hydrogel stabilizers: Small molecules that reinforce FG-repeat cohesion against DPR disruption
- Nuclear import enhancers: Compounds that boost transport receptor affinity for cargo, partially compensating for reduced NPC function
- Oxidative damage prevention: Antioxidant strategies to protect NUP98 from age-dependent carbonylation
Biomarker Applications
- NUP98 fragments in CSF as markers of NPC degradation
- NPC morphology assessment via nanobody-based imaging in patient-derived neurons
- NUP98 autoantibodies as potential peripheral biomarkers
Key Research Findings
- Hülsmann et al. (2012) established that NUP98 FG-domains form the primary selective barrier through hydrogel formation[@hlsmann2012]
- Jovičić et al. (2015) identified nucleoporins including NUP98 as genetic modifiers of C9orf72 DPR toxicity in yeast[@jovii2015]
- Shi et al. (2017) demonstrated direct phase separation of NUP98 with poly(PR) dipeptides[@shi2017]
- Eftekharzadeh et al. (2018) showed that tau directly disrupts NPCs by binding NUP98 in AD[@eftekharzadeh2018]
- D'Angelo et al. (2009) revealed age-dependent NPC deterioration as a fundamental feature of post-mitotic cell aging[@dangelo2009]
See Also
- [NUP62](/genes/nup62) — Central channel FG-nucleoporin, also disrupted in neurodegeneration
- [C9orf72](/genes/c9orf72) — Hexanucleotide repeat expansion gene causing ALS/FTD
- [TDP-43](/genes/tardbp) — RNA-binding protein dependent on NPC integrity
- [MAPT (Tau)](/genes/mapt) — [Tau protein](/proteins/tau) disrupts NPCs in tauopathies
- [Nuclear Transport Defects in Neurodegeneration](/mechanisms/nuclear-transport-defects)
- [Amyotrophic Lateral Sclerosis](/diseases/als)
- [Frontotemporal Dementia](/diseases/ftd)
External Links
- [NCBI Gene: NUP98](https://www.ncbi.nlm.nih.gov/gene/4928)
- [UniProt: P52948](https://www.uniprot.org/uniprot/P52948)
- [GeneCards: NUP98](https://www.genecards.org/cgi-bin/carddisp.pl?gene=NUP98)
- [OMIM: 601021](https://omim.org/entry/601021)
- [Allen Brain Atlas: NUP98](https://portal.brain-map.org/explore/genes?searchType=gene&query=NUP98)
References
[Jovičić A et al, Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS (2015)](https://pubmed.ncbi.nlm.nih.gov/26317592/)
[Kalverda B et al, Nucleoporins directly stimulate expression of developmental and cell-cycle genes inside the nucleoplasm (2010)](https://pubmed.ncbi.nlm.nih.gov/20478258/)
[Toyama BH et al, Identification of long-lived proteins reveals exceptional stability of essential cellular structures (2013)](https://pubmed.ncbi.nlm.nih.gov/24315098/)
[Shi KY et al, Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export (2017)](https://pubmed.ncbi.nlm.nih.gov/28211479/)
[Zhang K et al, The C9orf72 repeat expansion disrupts nucleocytoplasmic transport (2015)](https://pubmed.ncbi.nlm.nih.gov/26317591/)
[Freibaum BD et al, GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport (2015)](https://pubmed.ncbi.nlm.nih.gov/26317593/)
[Eftekharzadeh B et al, Tau protein disrupts nucleocytoplasmic transport in Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29420260/)
[Grima JC et al, Mutant huntingtin disrupts the nuclear pore complex (2017)](https://pubmed.ncbi.nlm.nih.gov/28861249/)
[D'Angelo MA et al, Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells (2009)](https://pubmed.ncbi.nlm.nih.gov/19135897/)
[Hülsmann BB et al, The permeability of reconstituted nuclear pores provides direct evidence for the selective phase model (2012)](https://pubmed.ncbi.nlm.nih.gov/22939624/)Pathway Diagram
The following diagram shows the key molecular relationships involving NUP98 — Nucleoporin 98 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)