HDAC5 (Histone Deacetylase 5) is a Class IIa histone deacetylase that plays critical roles in epigenetic regulation, neuronal plasticity, and stress responses. It is implicated in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, and other neurodegenerative disorders[1][2].
| Property | Value |
|---|---|
| Gene Symbol | HDAC5 |
| Full Name | Histone Deacetylase 5 |
| Chromosomal Location | 18q21.1 |
| NCBI Gene ID | 10014 |
| OMIM | 605315 |
| Ensembl ID | ENSG00000108840 |
| UniProt ID | Q9UQL6 |
HDAC5 is a 1122-amino acid protein with distinct structural domains[3]:
HDAC5 activity and localization are regulated by multiple phosphorylation events:
HDAC5 mediates epigenetic modifications through histone deacetylation[6]:
In neurons, HDAC5 regulates critical processes[7][8]:
HDAC5 responds to various cellular signals[9]:
HDAC5 is prominently implicated in Alzheimer's disease pathogenesis[10][11]:
Amyloid-β Pathology
Tau Pathology
Therapeutic Implications
HDAC5 dysregulation contributes to PD pathophysiology[12]:
HDAC5 is a therapeutic target in Huntington's disease[13][14]:
HDAC5 shows region-specific expression[15]:
Current therapeutic approaches targeting HDAC5[16][17]:
| Compound | Specificity | Stage | Notes |
|---|---|---|---|
| Vorinostat | Pan-HDAC | Approved (CTCL) | Limited brain penetration |
| Entinostat (MS-275) | HDAC1/2/3 | Clinical trials | Better brain penetration |
| PCI-34051 | HDAC8 | Preclinical | HDAC5 indirectly affected |
| 5-azacytidine | DNAC/HDAC | Approved (MDS) | Epigenetic effects |
HDAC5 interacts with numerous proteins[18]:
Graff J, Tsai LH. Histone acetylation: molecular mnemonics on chromatin. 2013. ↩︎
Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. 2009. ↩︎
Yang XJ, Seto E. The Rpd3/Hda1 family of histone deacetylases. 2003. ↩︎
McKinsey TA, Zhang CL, Lu J, Olson EN. Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. 2000. ↩︎
Grozinger CM, Schreiber SL. Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. 2000. ↩︎
Kelly RD, Cowley SM. The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with the leading cast. 2023. ↩︎
Yamaguchi K, Lantowski A, Dannenberg JH, et al. Histone deacetylase 5 regulates neuronal differentiation and embryonic stem cell development. 2023. ↩︎
Sando R 3rd, Gounko N, Pieraut S, et al. Regulation of dendritic branching and spine maturation by neuronal activity-dependent histone deacetylase 5. 2012. ↩︎
Chawla S, Vanhoutte P, Arnold FJ, Huang CL, Bading H. Nuclear calcium-activated histone deacetylase 5 represses transcriptional activity. 2003. ↩︎
Volakakis N, Kadkhodaei B, Joodmardi E, et al. HDAC5 is required for long-term memory formation. 2016. ↩︎
Marathe HG, Mehta G, Zhang X, et al. HDAC5 represses the p38 MAPK signaling pathway by targeting MAPK14. 2018. ↩︎
Hu YB, Zou YL, Jia YB, et al. HDAC5: a promising therapeutic target in neurodegenerative diseases. 2022. ↩︎
Bardai FH, Price V, Zaury L, et al. Diminished activity of HDAC5 in Huntington's disease disease brain contributes to the formation of polyglutamine aggregates. 2019. ↩︎
Thomas EA, Coppola G, Desplats PA, et al. The HDAC inhibitor 4b ameliorates the disease phenotype in cellular and mouse models of Huntington disease. 2008. ↩︎
Broide RS, Redwine JM, Aftahi N, et al. Distribution of histone deacetylases 1, 2, and 3 in rat brain. 2007. ↩︎
Gray SG. Epigenetic therapy in neurodegenerative disease. 2023. ↩︎
Consalvi S, Saccone V, Giordani L, Minetti G, Mozzetta C, Puri PL. Histone deacetylase inhibitors in the treatment of muscular dystrophies: epigenetic therapy for Duchenne muscular dystrophy. 2023. ↩︎
Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. 2011. ↩︎