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, Alzheimer's disease, and other neurodegenerative conditions through its regulation of microtubule acetylation, oxidative stress, and metabolic homeostasis[1][2].
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.
| Property | Value |
|---|---|
| Symbol | SIRT2 |
| Full Name | Sirtuin 2 |
| Chromosomal Location | 19q13.32 |
| NCBI Gene ID | 22933 |
| OMIM | 604479 |
| Ensembl ID | ENSG00000145335 |
| UniProt ID | Q8IXJ6 |
| Gene Length | ~29 kb |
| Exons | 13 coding exons |
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.
SIRT2 possesses the conserved sirtuin catalytic domain comprising:
SIRT2 deacetylates alpha-tubulin at Lys40, regulating microtubule dynamics and stability. This function is critical for:
SIRT2 regulates cell cycle progression through:
SIRT2 modulates several metabolic pathways:
SIRT2 responds to various cellular stresses:
SIRT2 plays a complex role in alpha-synuclein pathology:
In PD models:
Recent studies show SIRT2 regulates neuroinflammation:
SIRT2 modulates tau pathology through:
SIRT2 affects amyloid-beta through:
SIRT2 levels increase with age and in AD brain:
In HD:
SIRT2 is expressed throughout the brain:
SIRT2 is also expressed in:
SIRT2 itself is regulated by acetylation:
SIRT2 activity is modulated by phosphorylation:
| Compound | Development Stage | Notes |
|---|---|---|
| AK-1 | Preclinical | First-generation, neuroprotective in PD models |
| AGK2 | Preclinical | Potent, good brain penetration |
| Tenovin-6 | Preclinical | Dual SIRT1/2 inhibitor |
| Compound 15c | Preclinical | Selective SIRT2 inhibitor |
SIRT2 inhibitors have shown neuroprotection in:
SIRT2 activators are being explored for:
No SIRT2-targeted therapies have reached clinical trials for neurodegeneration as of 2024.
SIRT2 removes acetyl groups from lysine residues using NAD+ as co-substrate, producing O-acetyl-ADP-ribose and nicotinamide. Key substrates include:
| Partner | Interaction | Functional Effect |
|---|---|---|
| Alpha-tubulin | Substrate | Microtubule regulation |
| FOXO1/3 | Deacetylation | Stress response |
| Cdc25C | Deacetylation | Cell cycle control |
| p53 | Deacetylation | Apoptosis |
| Parkin | Deacetylation | E3 ligase activity |
SIRT2 knockout mice are viable with mild phenotypes:
SIRT2-related biomarkers:
Key research priorities:
SIRT2 remains a compelling target for neuroprotective therapies due to its central role in multiple neurodegenerative pathways[li2023].
Outeiro TF, et al. Sirtuin 2 inhibitors prevent alpha-synuclein aggregation and protect dopaminergic neurons. Science. 2007. ↩︎ ↩︎
de Oliveira RM, et al. The mechanism of sirtuin 2 in Parkinson's disease. J Neurochem. 2017. ↩︎
Garske AL, et al. Sirt2 deacetylates tubulin and regulates mitotic exit in yeast. Nat Cell Biol. 2010. ↩︎
Donmez G, et al. SIRT2 and NAD+ in brain aging and neurodegeneration. Front Aging Neurosci. 2012. ↩︎
Zhang Y, et al. SIRT2 inhibition reduces neuroinflammation in Parkinson's disease models. J Neuroinflammation. 2023. ↩︎
Maxan A, et al. SIRT2 activity as a modifier in Alzheimer's disease. Neurobiol Aging. 2018. ↩︎
Wang Y, et al. Sirt2 regulates tau acetylation and pathology in Alzheimer's disease. Nat Neurosci. 2022. ↩︎
Kelley N, et al. Targeting SIRT2 in Huntington's disease: new insights. Nat Rev Drug Discov. 2022. ↩︎