SIRT2 Gene

SIRT2 Gene

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SIRT2 Gene</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>SIRT2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Sirtuin 2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19q13.32</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>22933</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604479</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000145335</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q8IXJ6</td>
</tr>
<tr>
<td class="label">Gene Length</td>
<td>~29 kb</td>
</tr>
<tr>
<td class="label">Exons</td>
<td>13 coding exons</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Development Stage</td>
</tr>
<tr>
<td class="label">AK-1</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">AGK2</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Tenovin-6</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Compound 15c</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">Alpha-tubulin</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">FOXO1/3</td>
<td>Deacetylation</td>
</tr>
<tr>
<td class="label">Cdc25C</td>
<td>Deacetylation</td>
</tr>
<tr>
<td class="label">p53</td>
<td>Deacetylation</t

SIRT2 Gene

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SIRT2 Gene</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>SIRT2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Sirtuin 2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19q13.32</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>22933</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604479</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000145335</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q8IXJ6</td>
</tr>
<tr>
<td class="label">Gene Length</td>
<td>~29 kb</td>
</tr>
<tr>
<td class="label">Exons</td>
<td>13 coding exons</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Development Stage</td>
</tr>
<tr>
<td class="label">AK-1</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">AGK2</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Tenovin-6</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Compound 15c</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">Alpha-tubulin</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">FOXO1/3</td>
<td>Deacetylation</td>
</tr>
<tr>
<td class="label">Cdc25C</td>
<td>Deacetylation</td>
</tr>
<tr>
<td class="label">p53</td>
<td>Deacetylation</td>
</tr>
<tr>
<td class="label">Parkin</td>
<td>Deacetylation</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">170 edges</a></td>
</tr>
</table>

SIRT2 (Sirtuin 2) is a NAD⁺-dependent deacetylase belonging to the sirtuin family of proteins. Located on chromosome 19q13.32, SIRT2 is primarily a cytoplasmic deacetylase that plays critical roles in cellular metabolism, stress response, and neurodegeneration. SIRT2 has been implicated in [Parkinson's disease](/diseases/parkinsons-disease), [Alzheimer's disease](/diseases/alzheimers-disease), and other neurodegenerative conditions through its regulation of microtubule acetylation, oxidative stress, and metabolic homeostasis[@outeiro2007][@deoliveira2017].

The sirtuin family comprises seven members (SIRT1-7) in mammals, all characterized by a conserved catalytic domain and NAD⁺-dependent deacetylase activity. SIRT2 is unique among sirtuins for its predominantly cytoplasmic localization and its role in regulating microtubule dynamics.

Gene Structure and Genomic Organization

The SIRT2 gene encodes a protein of 389 amino acids with a molecular weight of approximately 43 kDa. The protein contains the characteristic sirtuin catalytic domain and is expressed in both cytoplasmic and nuclear compartments.

Protein Structure and Function

Catalytic Domain

SIRT2 possesses the conserved sirtuin catalytic domain comprising:

• Rossmann-fold NAD⁺-binding domain: Binds NAD⁺ and the substrate
• Small subdomain: Contributes to substrate specificity
• His-Val-Asp (HVD) motif: Catalytic core for deacetylation

Subcellular Localization

• Primary: Cytoplasm, where it deacetylates alpha-tubulin
• Secondary: Nucleus under stress conditions (oxidative stress, DNA damage)
• Mitochondria: Under specific metabolic conditions

Normal Function

Microtubule Regulation

SIRT2 deacetylates alpha-tubulin at Lys40, regulating microtubule dynamics and stability. This function is critical for:

• Cell division and mitotic progression
• Neuronal morphology and axonal transport
• Cilia and flagella function
• Cell motility and migration[@garske2010]

Cell Cycle Control

SIRT2 regulates cell cycle progression through:

• Mitotic Entry: Deacetylates Cdc25C, promoting G2/M transition
• Mitotic Exit: Controls Aurora B kinase activity
• Cytokinesis: Regulates contractile ring formation

Metabolic Regulation

SIRT2 modulates several metabolic pathways:

• Glycolysis: Deacetylates glycolytic enzymes
• Lipogenesis: Regulates fatty acid synthesis
• Mitochondrial Function: Affects mitochondrial dynamics and quality
• Gluconeogenesis: Modulates PEPCK activity[@donmez2012]

Stress Response

SIRT2 responds to various cellular stresses:

• Oxidative Stress: Deacetylates FOXO transcription factors, enhancing antioxidant response
• Heat Shock: Regulates heat shock protein expression
• DNA Damage: Participates in DNA repair pathways
• ER Stress: Modulates unfolded protein response

Role in Parkinson's Disease

Alpha-Synuclein Toxicity

SIRT2 plays a complex role in alpha-synuclein pathology:

Dopaminergic Neuron Survival

In PD models:

• SIRT2 promotes death of dopaminergic neurons in response to oxidative stress
• SIRT2 inhibition protects against MPTP and 6-OHDA toxicity
• SIRT2 deacetylates parkin, affecting its E3 ligase activity
• Genetic variants may modify PD risk

Neuroinflammation

Recent studies show SIRT2 regulates neuroinflammation:

• SIRT2 inhibition reduces microglial activation
• Decreased pro-inflammatory cytokine production
• Potential therapeutic application in PD[@zhang2023]

Role in Alzheimer's Disease

Tau Pathology

SIRT2 modulates tau pathology through:

Amyloid-Beta Production

SIRT2 affects amyloid-beta through:

• BACE1 Regulation: SIRT2 deacetylates BACE1, affecting amyloid precursor protein (APP) processing
• Gamma-Secretase: Modulates presenilin activity
• Secretion: Affects Aβ release from neurons

Aging and AD

SIRT2 levels increase with age and in AD brain:

• Age-related SIRT2 upregulation contributes to neurodegeneration
• SIRT2 mediates caloric restriction benefits in brain aging
• SIRT2 activity affects cognitive function

Role in Other Neurodegenerative Diseases

Huntington's Disease

In HD:

• SIRT2 modifies mutant huntingtin aggregation
• SIRT2 inhibition reduces polyglutamine toxicity
• Modulates metabolic dysfunction in HD models
• Potential therapeutic target[@kelley2022]

Amyotrophic Lateral Sclerosis (ALS)

• Altered SIRT2 expression in motor neurons
• SIRT2 affects TDP-43 pathology
• Role in oxidative stress response

Multiple Sclerosis

• Demyelination associated with SIRT2 changes
• SIRT2 in oligodendrocyte function
• Potential for remyelination therapies

Expression Pattern

Brain Expression

SIRT2 is expressed throughout the brain:

• High Expression: Cerebral [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), striatum, cerebellum
• Cellular Distribution: [Neurons](/entities/neurons), oligodendrocytes, [microglia](/entities/microglia), [astrocytes](/entities/astrocytes)
• Subcellular: Predominantly cytoplasmic in neurons, translocates to nucleus under stress

Peripheral Tissues

SIRT2 is also expressed in:

• Liver: High metabolic activity
• Kidney: Tubular cells
• Muscle: Skeletal and cardiac muscle
• Adipose tissue

Post-Translational Modifications

Acetylation

SIRT2 itself is regulated by acetylation:

• p300/CBP: Acetylates SIRT2
• SIRT1: Deacetylates SIRT2 in stress conditions
• Autoregulation of deacetylase activity

Phosphorylation

SIRT2 activity is modulated by phosphorylation:

• CDK1: Phosphorylates SIRT2 during mitosis
• PKA: Modulates activity under metabolic stress
• AMPK: Responds to energy status

Therapeutic Targeting

SIRT2 Inhibitors

SIRT2 inhibitors have shown neuroprotection in:

• MPTP models of PD
• 6-OHDA models
• Alpha-synuclein transgenic models
• Aβ toxicity models

SIRT2 Activators

SIRT2 activators are being explored for:

• Alzheimer's disease
• Metabolic disorders
• Aging-related neurodegeneration

Clinical Status

No SIRT2-targeted therapies have reached clinical trials for neurodegeneration as of 2024.

Molecular Mechanisms

Deacetylase Activity

SIRT2 removes acetyl groups from lysine residues using NAD⁺ as co-substrate, producing O-acetyl-ADP-ribose and nicotinamide. Key substrates include:

• Alpha-tubulin: Microtubule stability
• FOXO transcription factors: Stress response
• p53: Apoptosis regulation
• Histone H4: Chromatin organization

Protein-Protein Interactions

Animal Models

Knockout Mice

• Increased microtubule acetylation
• Altered cell cycle progression
• Enhanced stress resistance

Transgenic Models

• SIRT2 overexpression in neurons
• Alpha-synuclein/SIRT2 double transgenic
• Tau/SIRT2 models

Biomarkers

SIRT2-related biomarkers:

• SIRT2 activity in patient-derived cells
• Alpha-tubulin acetylation status
• CSF SIRT2 levels (investigational)

Future Directions

Key research priorities:

SIRT2 remains a compelling target for neuroprotective therapies due to its central role in multiple neurodegenerative pathways[li2023].

See Also

• [SIRT1 Gene](/genes/sirt1)
• [SIRT3 Gene](/genes/sirt3)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Alpha-Synuclein Aggregation Pathway](/mechanisms/alpha-synuclein-pathology)
• [Tau Pathology Pathway](/mechanisms/tau-pathology)
• [Sirtuin Family Overview](/mechanisms/sirtuin-signaling)

External Links

• [NCBI Gene: SIRT2](https://www.ncbi.nlm.nih.gov/gene/22933)
• [UniProt: SIRT2](https://www.uniprot.org/uniprot/Q8IXJ6)
• [Allen Human Brain Atlas: SIRT2](https://human.brain-map.org/microarray/search/show?search_term=SIRT2)
• [OMIM: SIRT2](https://www.omim.org/entry/604479)

References

Pathway Context

Pathway Diagram

The following diagram shows the key molecular relationships involving SIRT2 Gene discovered through SciDEX knowledge graph analysis: