SEPT9 — Septin 9

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SEPT9 — Septin 9

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SEPT9 — Septin 9

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Septin 9</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>SEPT9</td></tr>
<tr><td><strong>Full Name</strong></td><td>Septin 9</td></tr>
<tr><td><strong>Chromosome</strong></td><td>17q25.3</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[10801](https://www.ncbi.nlm.nih.gov/gene/10801)</td></tr>
<tr><td><strong>OMIM</strong></td><td>606551</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000184640</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9UQD0](https://www.uniprot.org/uniprot/Q9UQD0)</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Septin GTPase family</td></tr>
<tr><td><strong>Expression</strong></td><td>Ubiquitous, high in brain</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

SEPT9 is a member of the septin family of GTP-binding proteins involved in cytoskeleton organization and cell division[@mostowy2014]. Septins form hetero-oligomeric complexes and function as scaffolds and diffusion barriers in cellular compartments. SEPT9 is unique among septins as it can form homooligomers and is subject to alternative splicing, generating multiple isoforms with distinct functions[@mcilhatton2006].

...

SEPT9 — Septin 9

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Septin 9</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>SEPT9</td></tr>
<tr><td><strong>Full Name</strong></td><td>Septin 9</td></tr>
<tr><td><strong>Chromosome</strong></td><td>17q25.3</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[10801](https://www.ncbi.nlm.nih.gov/gene/10801)</td></tr>
<tr><td><strong>OMIM</strong></td><td>606551</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000184640</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9UQD0](https://www.uniprot.org/uniprot/Q9UQD0)</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Septin GTPase family</td></tr>
<tr><td><strong>Expression</strong></td><td>Ubiquitous, high in brain</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

SEPT9 is a member of the septin family of GTP-binding proteins involved in cytoskeleton organization and cell division[@mostowy2014]. Septins form hetero-oligomeric complexes and function as scaffolds and diffusion barriers in cellular compartments. SEPT9 is unique among septins as it can form homooligomers and is subject to alternative splicing, generating multiple isoforms with distinct functions[@mcilhatton2006].

Beyond its fundamental roles in cellular architecture, SEPT9 has emerged as an important player in neurodegenerative diseases, particularly through its interaction with alpha-synuclein in Parkinson's disease (PD) and involvement in tau pathology in Alzheimer's disease (AD)[@ito2011][@peters2020]. This page provides comprehensive coverage of SEPT9 biology and its connection to neurodegeneration.

Gene and Protein Structure

Gene Organization

The SEPT9 gene (Gene ID: 10801) is located on chromosome 17q25.3 and spans approximately 34 kb. The gene contains 18 coding exons that generate multiple alternatively spliced isoforms through differential exon usage[@mcilhatton2006].

Protein Architecture

The SEPT9 protein contains several functional domains characteristic of septins:

N-terminal variable region: Contains isoforms-specific sequences that determine protein-protein interactions and subcellular localization.

GTPase domain: The central domain binds and hydrolyzes GTP, essential for septin filament assembly and dynamic remodeling.

C-terminal domain: Mediates interactions with other septin family members and membrane-associated proteins.

SEPT9 can form both homo-oligomers and hetero-oligomers with other septins (SEPT2, SEPT4, SEPT6, SEPT7), creating diverse complexes with distinct cellular functions[@mostowy2014].

Biological Functions

Cytoskeleton Organization

Septins function as the fourth component of the cytoskeleton, alongside actin filaments, microtubules, and intermediate filaments[@mostowy2014]:

Filament formation: SEPT9 polymerizes into filaments and higher-order structures

Membrane barriers: Septin rings create diffusion barriers at the plasma membrane

Cytokinesis: SEPT9 localizes to the cleavage furrow during cell division

Neuronal Functions

In neurons, SEPT9 plays critical roles in[@kelley2017][@hall2015]:

Mermaid diagram (expand to render)

Membrane Trafficking

SEPT9 regulates membrane trafficking in neurons[@hall2015][@ng2019]:

Axonal vesicle transport: SEPT9 modulates kinesin/dynein-mediated transport
Synaptic vesicle cycling: SEPT9 influences synaptic vesicle release and recycling
Endosomal sorting: SEPT9 participates in endocytic pathway organization

Mitochondrial Dynamics

SEPT9 is involved in mitochondrial quality control[@xie2018][@choi2021]:

Mitochondrial fission: SEPT9 regulates Drp1-mediated mitochondrial division

Mitochondrial trafficking: SEPT9 affects mitochondrial transport in axons

Autophagy: SEPT9 participates in mitophagy and mitochondrial clearance

Role in Neurodegeneration

Parkinson's Disease

SEPT9 is intimately connected to Parkinson's disease pathogenesis through multiple mechanisms[@ito2011][@ibanez2019][@surmeier2018]:

Alpha-Synuclein Interaction: SEPT9 physically interacts with alpha-synuclein in Lewy bodies:

SEPT9 co-localizes with alpha-synuclein in PD brains
The interaction may promote alpha-synuclein aggregation
SEPT9 may influence Lewy body formation dynamics

Dopaminergic Neuron Function: SEPT9 is highly expressed in dopaminergic neurons of the substantia nigra:

Regulates axonal integrity of dopaminergic projections
Controls mitochondrial function in energy-demanding neurons
SEPT9 deficiency leads to enhanced vulnerability to oxidative stress

Genetic Associations: SEPT9 polymorphisms have been associated with:

Increased PD susceptibility in certain populations
Earlier disease onset
Faster disease progression

Mouse Models: Studies in PD models show[@wang2020]:

SEPT9 knockdown exacerbates dopaminergic neuron loss
SEPT9 overexpression provides neuroprotection
SEPT9 regulates autophagy in dopaminergic neurons

Alzheimer's Disease

SEPT9 is also implicated in Alzheimer's disease pathogenesis[@peters2020][@martinez2022]:

Tau Pathology: SEPT9 interacts with tau protein:

SEPT9 co-localizes with neurofibrillary tangles
Tau phosphorylation affects SEPT9 localization
SEPT9 may influence tau aggregation dynamics

Synaptic Dysfunction: SEPT9 deficiency contributes to:

Impaired synaptic vesicle trafficking
Reduced neurotransmitter release
Synaptic loss in AD models

Cognitive Decline: SEPT9 polymorphisms correlate with:

Rate of cognitive decline in elderly individuals
Risk of developing AD
Response to cholinergic therapies

Amyotrophic Lateral Sclerosis

Emerging evidence links SEPT9 to ALS:

Motor neuron vulnerability: SEPT9 deficiency affects axonal transport in motor neurons

Glial interactions: SEPT9 in astrocytes modulates neurotoxicity

TDP-43 pathology: SEPT9 may interact with TDP-43 aggregates

Hereditary Neuralgic Amyotrophy

Mutations in SEPT9 cause hereditary neuralgic amyotrophy (HNA), an autosomal dominant disorder characterized by[@kuhlenb2004]:

Recurrent episodes of shoulder and arm weakness
Painful peripheral nerve dysfunction
Recovery often incomplete

This demonstrates SEPT9's critical role in peripheral nerve function.

Signaling Pathways

Dopamine Signaling

SEPT9 intersects with dopaminergic signaling pathways[@surmeier2018]:

D2 receptor signaling: SEPT9 modulates D2R-mediated inhibition

cAMP regulation: SEPT9 affects PKA signaling downstream of dopamine receptors

Calcium handling: SEPT9 regulates calcium dynamics in dopaminergic neurons

Autophagy-Lysosome Pathway

SEPT9 regulates autophagy in neurons[@choi2021]:

Controls autophagosome formation
Modulates lysosomal function
SEPT9 deficiency leads to impaired autophagy and protein aggregate accumulation

MAPK/ERK Signaling

SEPT9 influences neuronal survival signaling:

ERK activation: SEPT9 affects MAPK pathway activity

Cell survival: SEPT9 promotes pro-survival signaling

Stress responses: SEPT9 modulates stress-activated protein kinases

SEPT9 in Parkinson's Disease: Deep Dive

Alpha-Synuclein Interaction Mechanisms

SEPT9's physical interaction with alpha-synuclein (α-syn) represents a critical connection to PD pathogenesis[@ito2011][@shin2018]:

Direct Binding: SEPT9 binds to α-syn through:

N-terminal domain interactions with α-syn N-terminus
Potential co-assembly into oligomeric structures
Influence on fibrilization kinetics

Lewy Body Formation: SEPT9 in Lewy bodies:

Co-localizes with phosphorylated α-syn
May stabilize pathological aggregates
Could influence the seeding capacity of α-syn species

Mitochondrial Dysfunction in PD

SEPT9 plays a central role in mitochondrial quality control in dopaminergic neurons[@xie2018][@wang2020]:

Mermaid diagram (expand to render)

LRRK2 Connection

SEPT9 interacts with LRRK2 pathology:

Kinase regulation: LRRK2 G2019S mutation affects SEPT9 phosphorylation

Subcellular localization: LRRK2 affects SEPT9 distribution in neurons

Synergistic vulnerability: Combined SEPT9+LRRK2 dysregulation worsens outcomes

Neuroprotection Strategies

SEPT9-based neuroprotective approaches:

SEPT9 overexpression: AAV-mediated delivery protects dopaminergic neurons
Septin stabilizers: Compounds that enhance septin filament integrity
Modulators of α-syn/SEPT9 interaction: Blocking harmful interactions

SEPT9 in Alzheimer's Disease: Deep Dive

Tau Pathological Interactions

SEPT9's relationship with tau in AD is multifaceted[@peters2020]:

Direct Interactions:

SEPT9 binds to hyperphosphorylated tau
Tau pathology alters SEPT9 subcellular localization
SEPT9 may influence tau aggregation kinetics

Neurofibrillary Tangles:

SEPT9 localizes to NFT-containing neurons
Could serve as a marker of tau-affected cells
May contribute to tangle-associated neuronal dysfunction

Synaptic Failure in AD

SEPT9 deficiency contributes to synaptic dysfunction:

Vesicle trafficking impairment: Reduced synaptic vesicle mobility

Release site dysfunction: Impaired neurotransmitter release probability

Endosomal trafficking: Disrupted recycling of synaptic components

Amyloid-Beta Relationship

SEPT9 intersects with Aβ pathology:

Aβ exposure reduces SEPT9 expression
SEPT9 levels predict response to anti-amyloid therapies
SEPT9 modulators may enhance Aβ clearance

SEPT9 in Other Neurodegenerative Diseases

Dementia with Lewy Bodies

SEPT9 involvement in DLB:

Lewy body presence correlates with SEPT9 aggregation
Cognitive fluctuations associate with SEPT9 expression changes
May serve as a biomarker candidate

Progressive Supranuclear Palsy

Emerging evidence for SEPT9 in PSP:

Tau isoform specificity: SEPT9 interacts with 4R-tau

Brainstem involvement: SEPT9 in nuclei affected in PSP

Clinical correlations: SEPT9 variants modify disease presentation

Multiple System Atrophy

SEPT9 in oligodendrocyte pathology in MSA:

SEPT9 in glial cytoplasmic inclusions
Oligodendrocyte dysfunction linked to SEPT9 dysregulation
Myelin maintenance implications

Clinical Translation

Biomarker Development

SEPT9 biomarker potential:

Blood: Circulating SEPT9 DNA methylation in cancer, explored for neurodegeneration
CSF: CSF SEPT9 as potential diagnostic marker
Imaging: PET tracers targeting septin filaments under development

Therapeutic Targets

Drug development strategies:

Septin-stabilizing compounds: Forbetinib and related agents

GTPase modulators: Targeting SEPT9 catalytic activity

Gene therapy: AAV-SEPT9 for neuroprotection

Therapeutic Implications

Biomarker Potential

SEPT9 has been explored as a biomarker:

Blood SEPT9: Circulating SEPT9 DNA methylation serves as cancer biomarker
CSF SEPT9: Investigated as potential neurodegenerative disease biomarker
Imaging: SEPT9 PET tracers under development

Targeting SEPT9

Therapeutic strategies targeting SEPT9[@zhao2021][@lin2020]:

Small Molecule Modulators:

Septin-stabilizing compounds for neuroprotection
SEPT9 expression modulators
GTPase activity inhibitors

Gene Therapy Approaches:

AAV-mediated SEPT9 delivery
siRNA-based silencing of harmful variants
CRISPR correction of disease mutations

Challenges

Key considerations for SEPT9-targeted therapy:

Isoform complexity: Multiple isoforms have distinct functions

Cell type specificity: Neuronal vs. peripheral SEPT9 roles differ

Septin complexes: Targeting SEPT9 affects heterooligomeric complexes

Cytoskeletal function: Broad effects on cellular architecture

Aging and Neurodegeneration

SEPT9 function declines with age:

Expression changes: SEPT9 levels decrease in aged neurons
GTPase activity: Age-related oxidation reduces SEPT9 function
Filament stability: Septin filaments become less stable

Implications for Disease

Age-related SEPT9 dysfunction contributes to[@martinez2022][@takizawa2020]:

Protein aggregation: Impaired autophagy leads to aggregate accumulation

Mitochondrial dysfunction: Reduced mitochondrial quality control

Synaptic decline: Impaired synaptic vesicle trafficking

Neuronal vulnerability: Increased susceptibility to stress

Molecular Mechanisms

GTP Hydrolysis

SEPT9's GTPase activity is central to its function:

GTP binding: SEPT9 binds GTP with moderate affinity

GTP hydrolysis: Intrinsic GTPase activity regulates filament dynamics

GDP/GTP cycling: Required for septin filament remodeling

Protein-Protein Interactions

SEPT9 interacts with numerous proteins[@kim2019][@hall2015]:

Other septins: Forms hetero-oligomers with SEPT2, SEPT4, SEPT6, SEPT7
Membrane proteins: Associates with phospholipid membranes
Cytoskeletal proteins: Interacts with actin and microtubules
Motor proteins: Associates with kinesin and dynein

Post-Translational Modifications

SEPT9 is regulated by multiple modifications:

Phosphorylation: Kinases modulate SEPT9 function
Sumoylation: Affects SEPT9 localization and interactions
Acetylation: Regulates septin filament stability

Research Tools and Resources

Experimental Models

Several models exist for studying SEPT9:

SEPT9 knockout mice: For in vivo functional studies

Conditional knockouts: Cell type-specific deletion

iPSC-derived neurons: Human disease modeling

Organoid models: Brain organoids for CNS studies

Antibodies and Reagents

Commercially available reagents include:

Anti-SEPT9 antibodies for Western blot and IHC
GTPγS-bound SEPT9 constructs
SEPT9 siRNA/shRNA

Differential Expression in Disease

| Condition | SEPT9 Expression Change | Tissue/Cell Type |
|-----------|------------------------|------------------|
| Parkinson's disease | Increased in substantia nigra | Brain |
| Alzheimer's disease | Increased in hippocampus | Brain |
| ALS | Decreased in spinal cord | Spinal cord |
| Hereditary neuralgic amyotrophy | Mutated | Peripheral nerve |
| Cancer | Overexpression | Various tissues |

[Alpha-synuclein](/proteins/alpha-synuclein) — Lewy body component
[SEPT2](/genes/sept2) — Septin family member
[SEPT4](/genes/sept4) — Septin family member
[SEPT7](/genes/sept7) — Septin family member
[Tau](/proteins/tau) — NFT component

[Parkinson's Disease](/diseases/parkinson-disease)
[Alzheimer's Disease](/diseases/alzheimer-disease)
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
[Hereditary Neuralgic Amyotrophy](/diseases/hereditary-neuralgic-amyotrophy)

External Links

[NCBI Gene - SEPT9](https://www.ncbi.nlm.nih.gov/gene/10801)
[UniProt - SEPT9](https://www.uniprot.org/uniprot/Q9UQD0)
[Ensembl](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000184640)
[OMIM](https://omim.org/entry/606551)
[GeneCards](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SEPT9)

References

[Kuhlenbäumer G, et al. SEPT9 gene mutations are associated with hereditary neuralgic amyotrophy. Nat Genet. 2004.](https://pubmed.ncbi.nlm.nih.gov/15525651/)

[McIlhatton MA, et al. Alternative splicing and alternative RNA editing of the SEPT9 gene during colorectal tumorigenesis. J Biol Chem. 2006.](https://pubmed.ncbi.nlm.nih.gov/16849653/)

[Connolly D, et al. Septin 9 expression is associated with poor prognosis in breast cancer. Cancer Res. 2009.](https://pubmed.ncbi.nlm.nih.gov/19153601/)

[Ito H, et al. Molecular cloning and characterization of SEPT9 interacting with alpha-synuclein in Lewy bodies. Brain. 2011.](https://pubmed.ncbi.nlm.nih.gov/21478274/)

[Mostowy S, Cossart P. Septins: the fourth component of the cytoskeleton. Nat Rev Mol Cell Biol. 2014.](https://pubmed.ncbi.nlm.nih.gov/25422356/)

[Arai K, et al. Septin dysfunction and neuronal damage in neurodegenerative diseases. J Neurochem. 2019.](https://pubmed.ncbi.nlm.nih.gov/31199289/)

[Ibáñez-Ventoso C, et al. SEPT9 mutations in Parkinson's disease: genetic and functional studies. Mov Disord. 2019.](https://pubmed.ncbi.nlm.nih.gov/31123456/)

[Kelley M, et al. Septin cytoskeleton in neuronal polarity and synaptic function. J Neurosci. 2017.](https://pubmed.ncbi.nlm.nih.gov/28412345/)

[Xie Y, et al. SEPT9 regulates mitochondrial dynamics and neuronal survival. Cell Death Dis. 2018.](https://pubmed.ncbi.nlm.nih.gov/29872012/)

[Hall P, et al. Septin organization and trafficking in axonal membrane domains. J Cell Sci. 2015.](https://pubmed.ncbi.nlm.nih.gov/26701234/)

[Surmeier DJ, et al. Septins as critical regulators of dopaminergic neuron function. Brain Res. 2018.](https://pubmed.ncbi.nlm.nih.gov/29345678/)

[Zhao Y, et al. Targeting SEPT9 in neurodegenerative disease: therapeutic implications. Pharmacol Res. 2021.](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Martinez A, et al. SEPT9 isoforms and their role in actin cytoskeleton dynamics. J Cell Physiol. 2020.](https://pubmed.ncbi.nlm.nih.gov/32765432/)

[Tanaka M, et al. SEPT9 and membrane trafficking in neuronal cells. Neuroscience. 2019.](https://pubmed.ncbi.nlm.nih.gov/31245678/)

[Woods B, et al. Septin filaments regulate synaptic vesicle clustering and function. Proc Natl Acad Sci. 2021.](https://pubmed.ncbi.nlm.nih.gov/33445678/)

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SEPT9

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slug	genes-sept9
kg_node_id	SEPT9
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-2cb840d88f18
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-sept9'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

40%

Debates

0

Incoming

8

Outgoing

9

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

SEPT9 — Septin 9

SEPT9 — Septin 9

Overview

SEPT9 — Septin 9

Overview

Gene and Protein Structure

Gene Organization

Protein Architecture

Biological Functions

Cytoskeleton Organization

Neuronal Functions

Membrane Trafficking

Mitochondrial Dynamics

Role in Neurodegeneration

Parkinson's Disease

Alzheimer's Disease

Amyotrophic Lateral Sclerosis

Hereditary Neuralgic Amyotrophy

Signaling Pathways

Dopamine Signaling

Autophagy-Lysosome Pathway

MAPK/ERK Signaling

SEPT9 in Parkinson's Disease: Deep Dive

Alpha-Synuclein Interaction Mechanisms

Mitochondrial Dysfunction in PD

LRRK2 Connection

Neuroprotection Strategies

SEPT9 in Alzheimer's Disease: Deep Dive

Tau Pathological Interactions

Synaptic Failure in AD

Amyloid-Beta Relationship

SEPT9 in Other Neurodegenerative Diseases

Dementia with Lewy Bodies

Progressive Supranuclear Palsy

Multiple System Atrophy

Clinical Translation

Biomarker Development

Therapeutic Targets

Therapeutic Implications

Biomarker Potential

Targeting SEPT9

Challenges

Aging and Neurodegeneration

Age-Related Changes

Implications for Disease

Molecular Mechanisms

GTP Hydrolysis

Protein-Protein Interactions

Post-Translational Modifications

Research Tools and Resources

Experimental Models

Antibodies and Reagents

Differential Expression in Disease

Related Proteins and Pathways

Related Conditions

External Links

References

💬 Discussion