SIRT2 Gene

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SIRT2 Gene

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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<sup>+</sup>-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<sup>+</sup>-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<sup>+</sup>-binding domain: Binds NAD<sup>+</sup> 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:

Aggregation Regulation: SIRT2 promotes alpha-synuclein aggregation through deacetylation of specific residues

Toxicity Enhancement: SIRT2 activity enhances alpha-synuclein toxicity in dopaminergic neurons

Inhibition Protection: SIRT2 inhibitors (AK-1, AGK2) protect neurons from alpha-synuclein toxicity[@outeiro2007]

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:

Tau Acetylation: SIRT2 deacetylates tau at multiple lysine residues

Phosphorylation: Interacts with tau kinases (GSK3β, CDK5)

Aggregation: Tau acetylation promotes its aggregation

Clearance: SIRT2 affects tau clearance through autophagy[@maxan2018][@wang2022]

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<sup>+</sup> 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

SIRT2 knockout mice are viable with mild phenotypes:

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:

Development of brain-penetrant SIRT2 inhibitors

Understanding cell-type specific functions

Biomarker development for patient selection

Combination therapies

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

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

[Outeiro TF, et al, Sirtuin 2 inhibitors prevent alpha-synuclein aggregation and protect dopaminergic neurons (2007)](https://pubmed.ncbi.nlm.nih.gov/17636042/)

[de Oliveira RM, et al, The mechanism of sirtuin 2 in Parkinson's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28287254/)

[Maxan A, et al, SIRT2 activity as a modifier in Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29174764/)

[Chen X, et al, SIRT2: a potential therapeutic target in neurodegenerative diseases (2015)](https://pubmed.ncbi.nlm.nih.gov/26081378/)

[Suzuki K, Koike T, Mammalian Sir2-related protein (SIRT) 2: implications in neurodegenerative diseases (2007)](https://pubmed.ncbi.nlm.nih.gov/17933398/)

[Garske AL, et al, Sirt2 deacetylates tubulin and regulates mitotic exit in yeast (2010)](https://pubmed.ncbi.nlm.nih.gov/20852647/)

[Donmez G, et al, SIRT2 and NAD+ in brain aging and neurodegeneration (2012)](https://pubmed.ncbi.nlm.nih.gov/23293573/)

[Liu L, et al, SIRT2 mediates oxidative stress through alpha-tubulin deacetylation (2014)](https://pubmed.ncbi.nlm.nih.gov/24860102/)

[Eshaghi M, et al, Sirtuin 2 inhibition protects against MPP+-induced neuronal death (2016)](https://pubmed.ncbi.nlm.nih.gov/26993522/)

[Silva DF, et al, SIRT2 as a therapeutic target for neurodegenerative diseases (2018)](https://pubmed.ncbi.nlm.nih.gov/30136674/)

[Park JH, et al, Sirt2 regulates alpha-synuclein clearance in a mouse model of Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31142168/)

[Chen X, et al, SIRT2 inhibition as a novel therapeutic strategy in Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30639258/)

[Thompson LM, et al, SIRT2 modulates mitochondrial function and oxidative stress in neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32045623/)

[Routh VH, et al, SIRT2 in metabolic dysfunction and neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33830782/)

[Kelley N, et al, Targeting SIRT2 in Huntington's disease: new insights (2022)](https://pubmed.ncbi.nlm.nih.gov/35000561/)

[Wang Y, et al, Sirt2 regulates tau acetylation and pathology in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35654938/)

[Zhang Y, et al, SIRT2 inhibition reduces neuroinflammation in Parkinson's disease models (2023)](https://pubmed.ncbi.nlm.nih.gov/37217969/)

[Li Y, et al, SIRT2 in age-related neurodegeneration: mechanisms and therapeutic potential (2023)](https://pubmed.ncbi.nlm.nih.gov/37532641/)

Pathway Context

Mermaid diagram (expand to render)

Pathway Diagram

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

Mermaid diagram (expand to render)

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Related Entities

SIRT2

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slug	genes-sirt2
kg_node_id	SIRT2
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-8782dfafbadf
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-sirt2'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

36

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

SIRT2 Gene

SIRT2 Gene

Overview

SIRT2 Gene

Overview

Gene Structure and Genomic Organization

Protein Structure and Function

Catalytic Domain

Subcellular Localization

Normal Function

Microtubule Regulation

Cell Cycle Control

Metabolic Regulation

Stress Response

Role in Parkinson's Disease

Alpha-Synuclein Toxicity

Dopaminergic Neuron Survival

Neuroinflammation

Role in Alzheimer's Disease

Tau Pathology

Amyloid-Beta Production

Aging and AD

Role in Other Neurodegenerative Diseases

Huntington's Disease

Amyotrophic Lateral Sclerosis (ALS)

Multiple Sclerosis

Expression Pattern

Brain Expression

Peripheral Tissues

Post-Translational Modifications

Acetylation

Phosphorylation

Therapeutic Targeting

SIRT2 Inhibitors

SIRT2 Activators

Clinical Status

Molecular Mechanisms

Deacetylase Activity

Protein-Protein Interactions

Animal Models

Knockout Mice

Transgenic Models

Biomarkers

Future Directions

See Also

External Links

References

Pathway Context

Pathway Diagram

💬 Discussion