SEPT9 — Septin 9

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:

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]:

Neuronal Functions

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

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]:

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

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

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

• 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

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

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

Amyotrophic Lateral Sclerosis

Emerging evidence links SEPT9 to ALS:

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

Signaling Pathways

Dopamine Signaling

SEPT9 intersects with dopaminergic signaling pathways[@surmeier2018]:

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:

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

• 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]:

LRRK2 Connection

SEPT9 interacts with LRRK2 pathology:

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

• 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:

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:

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:

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

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

Challenges

Key considerations for SEPT9-targeted therapy:

Aging and Neurodegeneration

Age-Related Changes

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]:

Molecular Mechanisms

GTP Hydrolysis

SEPT9's GTPase activity is central to its function:

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:

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 |

Related Proteins and Pathways

• [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

Related Conditions

• [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