Sirt2 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
SIRT2 (Sirtuin 2) is a NAD+-dependent deacetylase primarily localized to the cytoplasm where it deacetylates tubulin and regulates microtubule dynamics. It is implicated in aging, neurodegeneration, and cancer. SIRT2 has emerged as a therapeutic target for Parkinson's disease and other neurodegenerative conditions.
SIRT2 is one of seven mammalian sirtuins, a family of NAD+-dependent deacetylases/ADP-ribosyltransferases. Unlike SIRT1, which is primarily nuclear, SIRT2 shuttles between cytoplasm and nucleus and is the major cytoplasmic sirtuin with important functions in microtubule regulation and cellular stress responses.
SIRT2 is a 389 amino acid protein:
- Rossmann fold core (aa 48-332): Catalytic deacetylase domain
- N-terminal region (aa 1-47): Regulatory domain
- C-terminal region (aa 333-389): Substrate binding
- Molecular weight: ~43 kDa
- NAD+-binding Rossmann fold
- Catalytic His-187 residue
- Substrate specificity for acetyl-lysine
- Post-translational modifications regulate activity
SIRT2 is expressed in various tissues including brain:
- Microtubule Deacetylation: Deacetylates α-tubulin
- Cell Cycle Regulation: Controls mitotic entry
- Metabolic Regulation: Modulates metabolic enzymes
- Oxidative Stress: Responds to oxidative damage
- Cytoskeletal Dynamics: Regulates microtubule stability
- Chromatin Regulation: Nuclear translocation during stress
- Cytoplasm: Primary location
- Nucleus: Translocates during stress
- Mitochondria: Some isoforms
- Associated with microtubules
SIRT2 is implicated in PD:
- α-Synuclein Acetylation: SIRT2 deacetylates α-synuclein
- Aggregation: Promotes aggregation in models
- Genetic Variants: Some associated with PD risk
- Therapeutic Target: SIRT2 inhibition protective
- Modulates tau acetylation
- Affects amyloid pathology
- Role in neuroinflammation
- Huntington's Disease: Alters mutant huntingtin toxicity
- ALS: Modulates TDP-43 pathology
- Stroke: Affects post-ischemic damage
- Oncoprotein in gliomas
- Tumor suppressor in other cancers
- Metabolic reprogramming
SIRT2-tubulin relationship:
- Deacetylates α-tubulin at Lys40
- Increases microtubule dynamics
- Affects cell division
- Modulates intracellular transport
SIRT2 in α-synucleinopathy:
- Deacetylates α-synuclein
- Promotes aggregation
- Inhibition reduces pathology in models
SIRT2 in cellular stress:
- Oxidative stress response
- Metabolic stress adaptation
- DNA damage response
- Heat shock response
| Strategy |
Status |
Notes |
| SIRT2 inhibitors |
Preclinical |
AGK2, AK-1 |
| Selective inhibitors |
Discovery |
Improve selectivity |
| Combination therapy |
Research |
With other sirtuins |
- AGK2: Commonly used in research
- AK-1: Brain-penetrant
- Cambinol: Dual SIRT1/2 inhibitor
- No current SIRT2-targeted CNS trials
- SIRT2 inhibitors in oncology trials
- Brain-penetrant inhibitors
- Isoform-specific functions
- Combination strategies
- Biomarker development
- SIRT2 knockout mice: Viable, mild phenotype
- Transgenic models: PD models
- Conditional knockouts: Brain-specific
- Outeiro et al. (2007) "SIRT2 in Parkinson's disease" Science[1]
- Maxwell et al. (2011) "SIRT2 inhibition and neuroprotection" Nat Chem Biol[2]
- Liu et al. (2019) "SIRT2 and α-synuclein" Nat Neurosci[3]
4.deOliveira et al. (2020) "SIRT2 in aging brain" Aging Cell[4]
The study of Sirt2 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
[1] SIRT2 promotes α-synuclein aggregation. PMID:17544413
[2] SIRT2 inhibition is neuroprotective. PMID:21343556
[3] SIRT2 deacetylates α-synuclein. PMID:30683690
[4] SIRT2 in brain aging. PMID:32096671