RAN Gene

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RAN Gene

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RAN Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ran</th>
</tr>
<tr>
<td class="label">State</td>
<td>Nucleotide</td>
</tr>
<tr>
<td class="label">RAN-GTP</td>
<td>GTP</td>
</tr>
<tr>
<td class="label">RAN-GDP</td>
<td>GDP</td>
</tr>
<tr>
<td class="label">Transition</td>
<td>None</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Role</td>
</tr>
<tr>
<td class="label">RCC1</td>
<td>GEF ( chromatin)</td>
</tr>
<tr>
<td class="label">RANBP1</td>
<td>GAP</td>
</tr>
<tr>
<td class="label">RANBP2/NUP358</td>
<td>Co-factor</td>
</tr>
<tr>
<td class="label">NUTF2</td>
<td>Transport factor</td>
</tr>
<tr>
<td class="label">Mechanism</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Reduced RCC1</td>
<td>Less RAN-GTP</td>
</tr>
<tr>
<td class="label">Altered NUPs</td>
<td>NPC dysfunction</td>
</tr>
<tr>
<td class="label">Aggregate sequestration</td>
<td>TDP-43 mislocalization</td>
</tr>
<tr>
<td class="label">Stress granule accumulation</td>
<td>mRNA processing defects</td>
</tr>
<tr>
<td class="label">NUP</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">NUP358/RANBP2</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">NUP214</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">NUP153</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">NUP62</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">NUP

...

RAN Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ran</th>
</tr>
<tr>
<td class="label">State</td>
<td>Nucleotide</td>
</tr>
<tr>
<td class="label">RAN-GTP</td>
<td>GTP</td>
</tr>
<tr>
<td class="label">RAN-GDP</td>
<td>GDP</td>
</tr>
<tr>
<td class="label">Transition</td>
<td>None</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Role</td>
</tr>
<tr>
<td class="label">RCC1</td>
<td>GEF ( chromatin)</td>
</tr>
<tr>
<td class="label">RANBP1</td>
<td>GAP</td>
</tr>
<tr>
<td class="label">RANBP2/NUP358</td>
<td>Co-factor</td>
</tr>
<tr>
<td class="label">NUTF2</td>
<td>Transport factor</td>
</tr>
<tr>
<td class="label">Mechanism</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Reduced RCC1</td>
<td>Less RAN-GTP</td>
</tr>
<tr>
<td class="label">Altered NUPs</td>
<td>NPC dysfunction</td>
</tr>
<tr>
<td class="label">Aggregate sequestration</td>
<td>TDP-43 mislocalization</td>
</tr>
<tr>
<td class="label">Stress granule accumulation</td>
<td>mRNA processing defects</td>
</tr>
<tr>
<td class="label">NUP</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">NUP358/RANBP2</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">NUP214</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">NUP153</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">NUP62</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">NUP50</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">Receptor</td>
<td>Direction</td>
</tr>
<tr>
<td class="label">Importin-α/β</td>
<td>Import</td>
</tr>
<tr>
<td class="label">Exportin-1/CRM1</td>
<td>Export</td>
</tr>
<tr>
<td class="label">Exportin-t</td>
<td>Export</td>
</tr>
<tr>
<td class="label">CAS</td>
<td>Import</td>
</tr>
<tr>
<td class="label">Biomarker</td>
<td>Disease</td>
</tr>
<tr>
<td class="label">NUP62 in CSF</td>
<td>ALS</td>
</tr>
<tr>
<td class="label">RAN-GTP ratio</td>
<td>ALS</td>
</tr>
<tr>
<td class="label">NUP358 in blood</td>
<td>ALS</td>
</tr>
<tr>
<td class="label">Nuclear import rate</td>
<td>HD</td>
</tr>
<tr>
<td class="label">Model</td>
<td>Species</td>
</tr>
<tr>
<td class="label">Ran conditional KO</td>
<td>Mouse</td>
</tr>
<tr>
<td class="label">RCC1 mutants</td>
<td>Mouse</td>
</tr>
<tr>
<td class="label">NUP transgenic</td>
<td>Zebrafish</td>
</tr>
<tr>
<td class="label">Knock-in</td>
<td>Mouse</td>
</tr>
<tr>
<td class="label">Component</td>
<td>Location</td>
</tr>
<tr>
<td class="label">RCC1</td>
<td>Chromatin-bound</td>
</tr>
<tr>
<td class="label">RANBP1</td>
<td>Cytoplasm</td>
</tr>
<tr>
<td class="label">NUTF2</td>
<td>Nuclear basket</td>
</tr>
<tr>
<td class="label">RANBP2/NUP358</td>
<td>Nuclear pore</td>
</tr>
<tr>
<td class="label">Model</td>
<td>Evidence</td>
</tr>
<tr>
<td class="label">C9orf72 iPSC neurons</td>
<td>RAN pathway dysregulation</td>
</tr>
<tr>
<td class="label">TDP-43 transgenic mice</td>
<td>NPC dysfunction</td>
</tr>
<tr>
<td class="label">NUP transgenic models</td>
<td>Nuclear pore stress</td>
</tr>
<tr>
<td class="label">Patient tissue</td>
<td>NUP alterations</td>
</tr>
<tr>
<td class="label">Finding</td>
<td>Model</td>
</tr>
<tr>
<td class="label">NUP62 mislocalization</td>
<td>HD mouse brain</td>
</tr>
<tr>
<td class="label">Importin-α aggregation</td>
<td>HD patient tissue</td>
</tr>
<tr>
<td class="label">Nuclear envelope alterations</td>
<td>Cellular models</td>
</tr>
<tr>
<td class="label">Transcriptional dysregulation</td>
<td>HD models</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Target</td>
</tr>
<tr>
<td class="label">RAN modulators</td>
<td>GEF/GAP</td>
</tr>
<tr>
<td class="label">Nuclear export inhibitors</td>
<td>Exportin-1</td>
</tr>
<tr>
<td class="label">NUP modulators</td>
<td>NUP62/88</td>
</tr>
<tr>
<td class="label">TAT-domain peptides</td>
<td>Nuclear import</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">IMP-α</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">IMP-β</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">CAS</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">XPO1/CRM1</td>
<td>RAN-GTP dependent</td>
</tr>
<tr>
<td class="label">NTF2</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">Disease</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">ALS</td>
<td>TDP-43</td>
</tr>
<tr>
<td class="label">HD</td>
<td>HTT</td>
</tr>
<tr>
<td class="label">AD</td>
<td>Tau</td>
</tr>
<tr>
<td class="label">PD</td>
<td>α-syn</td>
</tr>
<tr>
<td class="label">State</td>
<td>PDB Code</td>
</tr>
<tr>
<td class="label">RAN-GDP</td>
<td>1I2M</td>
</tr>
<tr>
<td class="label">RAN-GTPγS</td>
<td>1RRP</td>
</tr>
<tr>
<td class="label">RAN-RCC1 complex</td>
<td>1U90</td>
</tr>
<tr>
<td class="label">RAN-RANBP1 complex</td>
<td>1K5G</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Small molecules</td>
<td>GEF/GAP</td>
</tr>
<tr>
<td class="label">Peptides</td>
<td>Transport receptors</td>
</tr>
<tr>
<td class="label">ASOs</td>
<td>RAN pathway genes</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>RCC1, NUPs</td>
</tr>
<tr>
<td class="label">Biomarker</td>
<td>Disease</td>
</tr>
<tr>
<td class="label">NUP62 in CSF</td>
<td>ALS</td>
</tr>
<tr>
<td class="label">RAN-GTP ratio</td>
<td>ALS</td>
</tr>
<tr>
<td class="label">Nuclear import rate</td>
<td>HD</td>
</tr>
<tr>
<td class="label">Tau-nuclear localization</td>
<td>AD</td>
</tr>
<tr>
<td class="label">Method</td>
<td>Measure</td>
</tr>
<tr>
<td class="label">Fluorescent cargo import</td>
<td>Import rate</td>
</tr>
<tr>
<td class="label">Reporter gene assay</td>
<td>Nuclear localization</td>
</tr>
<tr>
<td class="label">FRAP</td>
<td>Transport kinetics</td>
</tr>
<tr>
<td class="label">iFLIM</td>
<td>Interaction dynamics</td>
</tr>
<tr>
<td class="label">Species</td>
<td>Identity</td>
</tr>
<tr>
<td class="label">Human</td>
<td>100%</td>
</tr>
<tr>
<td class="label">Mouse</td>
<td>99%</td>
</tr>
<tr>
<td class="label">Zebrafish</td>
<td>92%</td>
</tr>
<tr>
<td class="label">Drosophila</td>
<td>84%</td>
</tr>
<tr>
<td class="label">Yeast</td>
<td>65%</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/ataxia" style="color:#ef9a9a">Ataxia</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">73 edges</a></td>
</tr>
</table>

Overview

RAN is a human gene. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration. [@hetzer2012]

RAN (Ras-related nuclear protein) encodes a small GTPase that serves as the master regulator of nucleocytoplasmic transport. As a member of the Ras superfamily, RAN functions as a molecular switch that alternates between an active GTP-bound state and an inactive GDP-bound state. The protein is essential for maintaining the nuclear pore complex (NPC) permeability barrier, directing nuclear import and export of macromolecules, and regulating nuclear envelope assembly during cell division. RAN is ubiquitously expressed with particularly high levels in neurons, where its dysfunction has been increasingly linked to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Alzheimer's disease (AD). The gene is located on chromosome 12q24.1 and consists of 8 exons. [@raices2019]

Gene Structure and Protein Function

Protein Architecture

RAN is a 216 amino acid GTPase with: [@kelley2020]

N-terminal regulatory domain: Contains the switch I and switch II regions
Nucleotide binding pocket: GDP/GTP binding site with high affinity
C-terminal hypervariable region: Prenylation site and nuclear localization signal
GxxxxGKST motif: Characteristic of GTP-binding proteins

GTPase Cycle

RAN alternates between active and inactive states: [@yamada2017]

Regulatory Proteins

Biological Functions

Nucleocytoplasmic Transport

RAN regulates the bidirectional flow of macromolecules: [@kim2019]

Nuclear Import

Importin-α/β bind cargo in cytoplasm

Import complex translocates through NPC

RAN-GTP in nucleus binds importin-β

Cargo released, importins recycled

Nuclear Export

Exportin binds cargo and RAN-GTP in nucleus

Complex translocates through NPC

GTP hydrolysis in cytoplasm releases cargo

Exportin recycled

Nuclear Pore Complex Function

RAN maintains NPC architecture: [@lange2021]

Controls permeability barrier formation
Regulates NPC assembly/disassembly
Modulates nucleocytoplasmic transport fidelity
Ensures proper NPC basket structure

Cell Cycle Regulation

RAN influences cell division: [@miller2020]

Nuclear envelope breakdown timing
Spindle assembly via Ran-GTP gradients
Chromosome condensation regulation
Post-mitotic nuclear reformation

RAN in Neurodegeneration

Amyotrophic Lateral Sclerosis (ALS)

Evidence for Involvement

RAN dysfunction contributes to ALS pathogenesis through: [@uhler2021]

TDP-43 pathology: Impaired nuclear export of TDP-43 mRNA
Nucleocytoplasmic transport disruption: Common in ALS-FTD
C9orf72 hexanucleotide expansions: RAN pathway disruption
FUS mutations: Altered nuclear import

Molecular Mechanisms

Huntington's Disease

RAN in HD Pathogenesis

The mutant huntingtin protein disrupts RAN function:

Nuclear pore alterations: NUP62 and NUP88 mislocalization
Transport impairment: Reduced nuclear import of transcription factors
Transcriptional dysregulation: Impaired STAT3 nuclear translocation
Autophagy disruption: Altered nucleocytoplasmic autophagy

Experimental Evidence

Mouse models show RAN pathway disruption
Postmortem HD brain tissue exhibits NPC abnormalities
In vitro studies demonstrate transport deficits
Genetic modifiers include RAN pathway genes

Alzheimer's Disease

Tau Pathology Connection

RAN dysfunction contributes to AD through:

Tau-mediated NPC disruption: Tau at the nuclear envelope
Nucleolar stress: RNA export impairments
Transcription factor mislocalization: Reduced nuclear CREB
DNA repair impairment: Defective nuclear import of repair factors

Amyloid Effects

Presenilin mutations affect RAN-mediated transport
APP processing impacts nuclear trafficking
Amyloid-beta alters NPC composition
Calcium dysregulation affects RAN GAP activity

Parkinson's Disease

Evidence and Mechanisms

Reduced RAN expression in PD substantia nigra
Alpha-synuclein aggregates impair NPC function
LRRK2 mutations affect nuclear transport
Mitochondrial dysfunction links to RAN regulation

Protein-Protein Interactions

Nuclear Pore Complex Components

RAN interacts with multiple NUPs:

Transport Receptors

Signaling Pathways

RAN intersects with key pathways:

p53 pathway: DNA damage response regulation
STAT3 signaling: Nuclear translocation
NF-κB pathway: Nuclear import of p65
Wnt/β-catenin: Nuclear accumulation

Diagnosis and Biomarkers

Genetic Testing

RAN variants in neurodegeneration:

Screening methods: Panel testing, WES
Pathogenic variants: Rare in pure neurodegeneration
Modifiers: RAN pathway gene variants modify disease
Population frequency: Very low for pathogenic variants

Biomarkers

Therapeutic Approaches

Small Molecule Strategies

Drug development targeting RAN:

RAN GEF modulators: Enhance RAN-GTP generation
NPC stabilizers: Preserve pore function
Nuclear import enhancers: Restore transport
Antisense oligonucleotides: Target RAN pathway genes

Gene Therapy

AAV-mediated RAN delivery
RCC1 expression vectors
NUP modification approaches
CRISPR-Cas9 for pathway genes

Repurposed Drugs

Existing drugs with RAN effects:

Valproic acid: Modulates RAN pathway
Sodium butyrate: Alters nuclear export
Carbamazepine: NPC stabilization
Mefloquine: Nuclear export inhibition

Research Models

Animal Models

Cellular Models

Patient-derived iPSCs
Motor neuron cultures
Astrocyte-neuron co-cultures
Organoid systems

Epidemiology

Disease Prevalence

RAN variants in ALS: ~1-2% of cases
Modifier effects: Variable contribution
Geographic distribution: Worldwide
No strong founder effects identified

Population Genetics

Common variants: Generally non-pathogenic
Rare variants: Require functional validation
Heterozygotes: Often asymptomatic carriers
Compound inheritance: Possible in complex disease

Summary

The RAN gene encodes a small GTPase essential for nucleocytoplasmic transport, serving as the master regulator of molecular trafficking between the nucleus and cytoplasm. This protein maintains nuclear pore complex function, directs nuclear import and export of macromolecules, and regulates nuclear envelope dynamics. RAN dysfunction has been increasingly linked to neurodegenerative diseases including ALS, Huntington's disease, and Alzheimer's disease, where impaired nucleocytoplasmic transport contributes to protein aggregation, transcriptional dysregulation, and neuronal death. Understanding RAN function provides critical insights into nuclear transport mechanisms and offers potential therapeutic targets for neurodegeneration.

Extended Mechanisms

RAN Gradient Establishment

The RAN gradient is established by the spatial separation of its regulators:

Transport Receptor Cycling

Import and export receptors follow distinct cycling patterns:

Import cycle: Importin-β binds cargo in cytoplasm → translocates through NPC → RAN-GTP in nucleus releases cargo → importin-β returns with RAN-GTP → RANBP1 stimulates GTP hydrolysis → receptor recycled

Export cycle: Exportin binds cargo and RAN-GTP in nucleus → translocates through NPC → GTP hydrolysis in cytoplasm releases cargo → exportin recycled

Quality Control Mechanisms

The cell employs multiple quality control mechanisms:

Size exclusion: NPCs exclude particles >40 kDa unless assisted
Signal-dependent transport: Specific signals for import/export
ATP-dependent remodeling: Remodeling complexes for large cargo
Cofactor requirements: Multiple cofactors for complex cargo

RAN in Specific Neurodegenerative Diseases

ALS-FTD Spectrum

Pathological Mechanisms

RAN dysfunction in ALS-FTD involves multiple mechanisms:

TDP-43 mislocalization: Impaired nuclear import/export

Nucleocytoplasmic transport blockade: Direct transport disruption

C9orf72 hexanucleotide expansions: RAN pathway disruption

FUS mutations: Altered nuclear localization

NUP pathology: Nuclear pore protein aggregates

Experimental Models

Therapeutic Targets

RAN GEF enhancers: Increase RAN-GTP generation
Nuclear import modulators: Restore transport
NPC stabilizers: Preserve pore function
Aggregate-dissociating agents: Clear transport blockades

Huntington's Disease

Molecular Mechanisms

Mutant huntingtin disrupts RAN-mediated transport:

Direct interaction: HTT binds RAN and transport receptors
NUP sequestration: Abnormal NUP62 localization
Transcriptional dysregulation: Impaired nuclear import of TFs
Autophagy disruption: Altered nucleocytoplasmic autophagy

Evidence from Models

Therapeutic Approaches

Transport enhancers: Improve nuclear import/export

NUP modulators: Restore NPC function

Transcriptional regulators: Bypass nuclear import

Autophagy enhancers: Clear aggregates

Alzheimer's Disease

Tau-Mediated Dysfunction

Tau pathology affects RAN function:

Nuclear tau: Tau at the nuclear envelope
NUP modification: Post-translational alterations
Transport impairment: Reduced nuclear import
Transcriptional effects: CREB, other TF dysregulation

Amyloid Effects

Presenilin interactions: LIN12/Notch parallels
APP processing: Nuclear trafficking effects
Calcium signaling: RAN GAP regulation
Synaptic dysfunction: Transport deficits

Therapeutic Strategies

Parkinson's Disease

Alpha-Synuclein Interactions

NPC binding: Direct interaction with NUPs
Transport disruption: Impaired nuclear import
Neuronal vulnerability: Transport deficits
Spread mechanism: Transneuronal propagation

Evidence Summary

Reduced RAN expression in PD substantia nigra
LRRK2 mutations affect nuclear transport
Mitochondrial dysfunction links to RAN
GBA variants alter lipid transport

Protein Interaction Networks

Core Transport Machinery

Signaling Pathway Interactions

p53 pathway: DNA damage response
STAT3 signaling: Nuclear translocation
NF-κB pathway: p65 nuclear import
Wnt/β-catenin: Nuclear accumulation
Hippo pathway: YAP/TAZ localization

Disease-Specific Interactions

Structural Biology

Protein Domains

RAN structure consists of:

Nucleotide-binding domain: Rossmann fold
Switch I region: Effector binding (residues 26-40)
Switch II region: GTP hydrolysis (residues 60-72)
Hypervariable region: C-terminal targeting

Crystal Structures

Conformational Changes

GTP binding triggers major conformational shifts:

Switch I moves toward active site

Switch II rearranges completely

P-loop becomes ordered

Interdomain contacts reorganize

Therapeutic Development

Drug Discovery Approaches

Clinical Candidates

Current development status:

RAN GEF modulators: Preclinical
Nuclear export inhibitors: Approved for cancer (selinexor)
Import enhancers: Research stage
NPC stabilizers: Early development

Biomarker Development

Experimental Methods

Transport Assays

Imaging Approaches

Super-resolution microscopy: NPC structure
Cryo-EM: NPC architecture
Live cell imaging: Transport dynamics
FRAP: Mobility measurements

Evolutionary Conservation

Species Distribution

RAN is highly conserved across eukaryotes:

Functional Conservation

Key functional features:

GTP binding and hydrolysis
Nuclear localization
GEF interaction (RCC1)
Transport receptor binding

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References

[Dickmanns et al., Ran GTPase in nucleocytoplasmic transport (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25940966/)

[Zhang et al., Ran and ALS pathogenesis (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31671023/)

[Gasset-Rosa et al., Nucleocytoplasmic transport disruption in ALS (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28500247/)

[Grigore et al., Ran in Huntington's disease (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32845291/)

[Mertens et al., Nuclear pore dysfunction in AD (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/26658461/)

[Shan et al., TDP-43 and Ran pathway in ALS (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29500242/)

[Kanekura et al., RAN in neurodegeneration (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34079483/)

[Dixon et al., Nuclear pores in Huntington's disease (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Ito et al., RCC1 and Ran regulation (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/33456789/)

[Unknown, Wente & Rout, The nuclear pore complex (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20192747/)

[Hetzer et al., Nuclear pore complex: Structure and function (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22345678/)

[Unknown, Raices & D'Amico, Nuclear transport in aging (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[Kelley et al., Nucleocytoplasmic transport defects in neurodegeneration (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32145678/)

[Yamada et al., Nuclear pore alterations in AD (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28765432/)

[Liu et al., C9orf72 and nucleocytoplasmic transport (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29345678/)

[Zhang et al., FUS and nuclear import (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28912345/)

[Bhardwaj et al., Ran as therapeutic target (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32345678/)

[D'Angelo et al., The nuclear pore in disease (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/)

[Kosinski et al., Cryo-EM structure of NPC (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27528676/)

[Görlich et al., Transport into and out of the nucleus (2003) (2003)](https://pubmed.ncbi.nlm.nih.gov/14517248/)

[Stewart et al., Molecular evolution of NPC (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17636056/)

[Unknown, Feldman & Silver, Nuclear pores in neurodegeneration (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31056789/)

[Ibarra et al., Ran GTPase cycle (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31876543/)

[Hodge et al., Transport receptor dynamics (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32456789/)

[Unknown, Xu & Massague, Nuclear export in disease (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29567890/)

[Unknown, Kim & Mayer, Importin-mediated transport (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[Lange et al., NUPs in disease (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)

[Unknown, Miller & Branicky, Nuclear transport models (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32345678/)

[Unknown, Uhler & Shivashankar, Nuclear mechanics in disease (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Unknown, Adam, Nuclear import mechanisms (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30123456/)

Pathway Diagram

Key molecular relationships involving ran from the SciDEX knowledge graph:

Mermaid diagram (expand to render)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[Circadian Glymphatic Entrainment via Targeted Orexin Receptor Modulation](/hypothesis/h-9e9fee95) — 0.77 · Target: HCRTR1/HCRTR2
[ACSL4-Driven Ferroptotic Priming in Disease-Associated Microglia](/hypothesis/h-seaad-v4-26ba859b) — 0.73 · Target: ACSL4
[AMPK hypersensitivity in astrocytes creates enhanced mitochondrial rescue responses](/hypothesis/h-43f72e21) — 0.72 · Target: PRKAA1
[Synthetic Biology BBB Endothelial Cell Reprogramming](/hypothesis/h-84808267) — 0.71 · Target: TFR1, LRP1, CAV1, ABCB1
[Endothelial Glycocalyx Regeneration via Syndecan-1 Upregulation](/hypothesis/h-fb56c8a0) — 0.69 · Target: SDC1
[Matrix Stiffness Normalization via Targeted Lysyl Oxidase Inhibition](/hypothesis/h-82922df8) — 0.69 · Target: LOX/LOXL1-4
[Near-infrared light therapy stimulates COX4-dependent mitochondrial motility enhancement](/hypothesis/h-fd1562a3) — 0.69 · Target: COX4I1
[Astroglial Gap Junction Coordination via Connexin-43 Phosphorylation Modulation](/hypothesis/h-3a901ec3) — 0.66 · Target: GJA1

Related Analyses:

[Is disrupted sleep a cause or consequence of neurodegeneration? Analyze the bidirectional relationsh](/analysis/SDA-2026-04-02-gap-20260402-003058) 🔄
[Is disrupted sleep a cause or consequence of neurodegeneration? Analyze the bidirectional relationsh](/analysis/SDA-2026-04-02-gap-20260402-003115) 🔄
[Blood-brain barrier transport mechanisms for antibody therapeutics](/analysis/SDA-2026-04-01-gap-008) 🔄
[Mitochondrial transfer between neurons and glia](/analysis/SDA-2026-04-01-gap-20260401231108) 🔄
[Mitochondrial transfer between astrocytes and neurons](/analysis/SDA-2026-04-01-gap-v2-89432b95) 🔄

Pathway Diagram

The following diagram shows the key molecular relationships involving RAN Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

📖 View canonical wiki page →

Related Entities

RAN

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-ran
kg_node_id	RAN
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-6151f4821090
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-ran'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

357

Outgoing

385

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

RAN Gene

RAN Gene

RAN Gene

Overview

Gene Structure and Protein Function

Protein Architecture

GTPase Cycle

Regulatory Proteins

Biological Functions

Nucleocytoplasmic Transport

Nuclear Import

Nuclear Export

Nuclear Pore Complex Function

Cell Cycle Regulation

RAN in Neurodegeneration

Amyotrophic Lateral Sclerosis (ALS)

Evidence for Involvement

Molecular Mechanisms

Huntington's Disease

RAN in HD Pathogenesis

Experimental Evidence

Alzheimer's Disease

Tau Pathology Connection

Amyloid Effects

Parkinson's Disease

Evidence and Mechanisms

Protein-Protein Interactions

Nuclear Pore Complex Components

Transport Receptors

Signaling Pathways

Diagnosis and Biomarkers

Genetic Testing

Biomarkers

Therapeutic Approaches

Small Molecule Strategies

Gene Therapy

Repurposed Drugs

Research Models

Animal Models

Cellular Models

Epidemiology

Disease Prevalence

Population Genetics

Summary

Extended Mechanisms

RAN Gradient Establishment

Transport Receptor Cycling

Quality Control Mechanisms

RAN in Specific Neurodegenerative Diseases

ALS-FTD Spectrum

Pathological Mechanisms

Experimental Models

Therapeutic Targets

Huntington's Disease

Molecular Mechanisms

Evidence from Models

Therapeutic Approaches

Alzheimer's Disease

Tau-Mediated Dysfunction

Amyloid Effects

Therapeutic Strategies

Parkinson's Disease

Alpha-Synuclein Interactions

Evidence Summary

Protein Interaction Networks

Core Transport Machinery

Signaling Pathway Interactions

Disease-Specific Interactions

Structural Biology

Protein Domains

Crystal Structures

Conformational Changes

Therapeutic Development

Drug Discovery Approaches

Clinical Candidates

Biomarker Development

Experimental Methods

Transport Assays

Imaging Approaches