Histone Deacetylases (Hdacs) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysine residues on histone proteins1, playing crucial
roles in epigenetic regulation of gene expression121. Beyond histone modification, HDACs target numerous non-histone proteins involved in neuronal function,
synaptic plasticity, and neurodegeneration2.
- HDAC1 (18q22): Primarily nuclear, expressed in most tissues
- HDAC2 (6q21): Neuronally enriched, critical for synaptic plasticity3
- HDAC3 (5q31): Expressed in brain, associated with transcriptional repression
- HDAC8 (Xp11.23): Primarily in smooth muscle and heart
- HDAC4 (2q37.3): Activity-dependent nuclear-cytoplasmic shuttling4
- HDAC5 (18q11): Neuronal activity-dependent function
- HDAC7 (12q13): Expressed in heart and skeletal muscle
- HDAC9 (7p15-p14): Expressed in brain and muscle
- HDAC6 (Xp11.23): Primarily cytoplasmic, deacetylates α-tubulin5
- HDAC10 (22q13): Lysosomal degradation
- SIRT1-7: Deacetylases with diverse cellular functions6
- HDAC11 (3p12): Least characterized
- Repress transcription by deacetylating histones
- Dynamic regulation of gene expression programs
- Critical for neuronal development and differentiation
- HDAC2 negatively regulates memory formation3
- HDAC2 and HDAC3 modulate synaptic plasticity
- Activity-dependent histone acetylation is crucial for LTP
- p53, NF-κB, STAT3
- α-Tubulin (HDAC6)
- Heat shock proteins
- HDAC2 is elevated in AD brain and correlates with memory deficits7
- HDAC6 aggregates in AD brain and affects tau pathology5
- Class I HDACs promote Amyloid-Beta production2
- HDAC inhibition improves memory in AD models8
- SIRT1 has neuroprotective effects6
- HDAC inhibitors protect dopaminergic neurons
- α-Synuclein acetylation affects aggregation
- HDAC inhibitors are therapeutic candidates9
- Mutant huntingtin interacts with HDACs
- Transcriptional dysregulation involves HDAC function
- HDAC levels altered in motor neurons
- HDAC inhibitors show promise in preclinical models10
Several HDAC inhibitors are being tested:
- VPA (Valproic Acid): Class I inhibitor, tested in AD and ALS
- SAHA (Vorinostat): Approved for cancer, being repurposed
- CI-994: Being investigated for neurodegenerative diseases
- Lack of brain-penetrant, isoform-selective inhibitors
- Side effects from broad HDAC inhibition
- Need for better understanding of isoform-specific functions
The study of Histone Deacetylases (Hdacs) 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.
- Gräff J, Tsai LH. Histone acetylation: molecular mnemonics on chromatin. Neuron. 2013;79(4):654-668.
- Dietz KC, Casaccia P. HDAC inhibitors and neurodegeneration: at the edge between magic bullets and magic poisons. Trends Neurosci. 2010;33(7):299-310.
- Xu K, Dai XL, Huang HC, et al. Targeting HDACs: a promising therapy for Alzheimer's Disease. Oxid Med Cell Longev. 2011;2011:143269.
- Johnson AA, Sathigramsiri K, Sheppard HM, et al. The role of HDACs in the response of the brain to metabolic stress. Front Cell Neurosci. 2022;16:983278.
- Simões-Pires C, Zwick V, Nurisso A, et al. HDAC6 as a target for neurodegenerative diseases: what makes it different from classical HDACs? J Alzheimers Dis. 2013;33(1):197-219.
- consolidation of memory. Nat Rev Neurosci. 2009;10(9):615-620.
- Sleiman SF, Basso M, Mahishi L, et al. Putting the 'kinase' in 'neurodegeneration': is HDAC a reasonable target? Expert Opin Ther Targets. 2009;13(5):569-571.
- Langley B, Gensert JM. Therapeutic targeting of REST in Huntington's Disease. Nat Med. 2014;20(3):239-240.
- Jia H, Morris CD, Williams RM, et al. HDAC6 inhibitor accelerates pathology and improves memory in a tauopathy mouse model. Acta Neuropathol Commun. 2019;7(1):133.
- Chuang DM, Leng Y, Marinova Z, et al. Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci. 2009;32(11):591-601.