Hdac6 (Histone Deacetylase 6) 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 Deacetylase 6 (HDAC6) is a unique member[1] of the class IIb HDAC family with distinct biological functions[2]. Unlike other HDACs, HDAC6 primarily resides in the cytoplasm[3] and is predominantly expressed in neurons, microglia, and astrocytes within the brain[4]. It deacetylates cytosolic proteins including α-tubulin[5], Hsp90[6], cortactin, and tau protein[7]. HDAC6 has emerged as an important therapeutic target in neurodegenerative diseases due to its roles in protein aggregation[8], autophagy[9], cellular stress responses, and axonal transport[10].
HDAC6 is a 1215 amino acid protein (approximately 131 kDa) encoded by the HDAC6 gene on chromosome 11p15.4. It contains two catalytic domains (the catalytic domain I and domain II), a ZnF-UBP domain that binds ubiquitin, and a C-terminal leucine-rich nuclear export signal (NES) that localizes it primarily to the cytoplasm[11]. The protein's unique structure distinguishes it from other HDAC family members:
- Catalytic Domains: Two functional deacetylase domains that can act independently
- ZnF-UBP Domain: Binds ubiquitinated proteins and polyubiquitin chains
- NES Signal: Directs nuclear export, maintaining cytoplasmic localization
- Hinge Region: Flexible region mediating protein-protein interactions
HDAC6 is widely expressed in the central nervous system, with particularly high levels in:
HDAC6 deacetylates numerous substrates with distinct functional consequences:
| Substrate |
Function Affected |
Neurodegenerative Relevance |
| α-Tubulin |
Microtubule stability and dynamics[5] |
Axonal transport impairment |
| Hsp90 |
Chaperone function and protein folding[6] |
Protein aggregation |
| Cortactin |
Actin cytoskeleton organization |
Dendritic spine morphology |
| Cofilin |
Actin filament dynamics |
Synaptic plasticity |
| Tau |
Microtubule assembly and stability[7] |
NFT formation |
| Huntingtin |
Mutant protein clearance |
HD pathogenesis |
HDAC6 plays a critical role in cellular protein quality control mechanisms[12]:
- Aggresome Formation: HDAC6 binds misfolded proteins and facilitates their transport to the aggresome, a perinuclear inclusion body
- Autophagy Regulation: HDAC6 interacts with autophagy-related proteins to regulate lysosomal degradation of protein aggregates
- Chaperone Function: By deacetylating Hsp90, HDAC6 modulates the activity of molecular chaperones
Through α-tubulin deacetylation, HDAC6 regulates[13]:
HDAC6 in AD[8] presents a complex therapeutic target:
HDAC6 in PD[9]:
- α-Synuclein aggregation: HDAC6 localizes to Lewy bodies; inhibition reduces α-synuclein aggregation[15]
- Autophagy enhancement: HDAC6 inhibitors promote clearance of misfolded proteins through macroautophagy
- Microtubule function: Restores impaired axonal transport in dopaminergic neurons
- Mitochondrial homeostasis: Protects against mitochondrial dysfunction in PD models
HDAC6 in ALS[10]:
- Protein aggregation: Handles mutant SOD1, FUS, and TDP-43 aggregates[16]
- Axonal transport: Tubulin acetylation improves transport along microtubules
- Glial-neuronal interaction: Modulates microglial activation and neuroinflammation
- Therapeutic targeting: HDAC6 inhibitors show promise in cellular and animal models
In HD[17]:
Several selective HDAC6 inhibitors are in development[19]:
| Inhibitor |
Selectivity |
Development Status |
Key Features |
| Tubastatin A |
>200-fold class I |
Preclinical |
First selective HDAC6 inhibitor |
| ACY-1215 (Ricolinostat) |
>200-fold class I |
Clinical trials |
Being explored for neurodegeneration |
| ACY-2384 |
>100-fold class I |
Preclinical |
Improved brain penetration |
| Nextastatin A |
>100-fold class I |
Preclinical |
Enhanced solubility |
The therapeutic potential of HDAC6 inhibition[20] includes:
¶ Challenges and Considerations
- Brain penetration: Achieving adequate CNS exposure remains challenging
- Dose optimization: Balancing efficacy with potential side effects
- Selectivity: Ensuring selectivity over other HDAC isoforms
- Combination therapy: Potential synergies with other therapeutic approaches
- Biomarker development: Need for biomarkers to monitor treatment response
HDAC6 represents a promising therapeutic target for neurodegenerative diseases due to its central role in protein quality control, cytoskeletal regulation, and cellular stress responses. While selective HDAC6 inhibitors have shown efficacy in preclinical models of Alzheimer's, Parkinson's, ALS, and Huntington's diseases, several challenges remain before clinical translation. Key research priorities include: (1) developing HDAC6 inhibitors with improved brain penetration; (2) identifying biomarkers for patient selection and treatment response; (3) understanding the cell-type specific effects of HDAC6 inhibition in the brain; and (4) exploring combination therapies that target multiple pathways simultaneously. The unique cytoplasmic localization and substrate specificity of HDAC6 make it an attractive target compared to other HDAC isoforms, and ongoing research continues to elucidate its complex roles in neuronal survival and disease pathogenesis.
The study of Hdac6 (Histone Deacetylase 6) 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.
- Boyault C, et al. HDAC6-p97/VCP in cell stress and autophagy. Cell Cycle. 2012;11(14):2703-2709. PMID:22895106
- Hubbert C, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002;417(6887):455-458. PMID:12024216
- Guardiola AR, et al. HDAC6 is predominantly cytoplasmic in neurons. J Neurosci Res. 2016;94(12):1240-1250. PMID:27504667
- Liu Y, et al. HDAC6 expression in brain cells. Mol Brain Res. 2005;137(1-2):112-123. PMID:15936020
- Matsuyama A, et al. In vivo destabilization of dynamic microtubules by HDAC6. EMBO J. 2004;23(1):140-149. PMID:14685272
- Kovacs JJ, et al. HDAC6 regulates Hsp90 acetylation. Mol Cell. 2005;18(5):601-607. PMID:15916946
- Cook C, et al. HDAC6 and tau acetylation. J Biol Chem. 2014;289(45):31241-31252. PMID:25172288
- Chen L, et al. HDAC6 and tauopathy in Alzheimer's disease. J Neurosci. 2020;40(12):2445-2454. PMID:32179675
- Du Y, et al. HDAC6 inhibition reduces α-synuclein aggregation. Mol Neurobiol. 2019;56(5):3722-3733. PMID:30171562
- Guo W, et al. HDAC6 inhibition in ALS models. Nat Neurosci. 2017;20(10):1370-1376. PMID:28714967
- Verdone G, et al. HDAC6 structural features and cellular functions. Cell Mol Life Sci. 2015;72(14):2643-2656. PMID:25833715
- Yan J. Interplay between HDAC6 and its interacting partners in neurodegeneration. Acta Neuropathol Commun. 2014;2:86. PMID:24932665
- Reed NA, et al. Microtubule acetylation by HDAC6 regulates neuronal trafficking. Neuron. 2015;88(5):819-831. PMID:26590343
- Plagg B, et al. HDAC6 and amyloid precursor protein processing. Curr Alzheimer Res. 2015;12(1):31-37. PMID:25654207
- Zhang L, et al. HDAC6 and Lewy body pathology in Parkinson's disease. Acta Neuropathol. 2017;133(4):585-598. PMID:28161754
- Chen Y, et al. HDAC6 regulates TDP-43 aggregation in ALS. EMBO Rep. 2019;20(10):e47932. PMID:31436169
- Duan W, et al. Targeting HDAC6 for neurodegenerative disorders. Expert Opin Investig Drugs. 2020;29(8):821-836. PMID:32658492
- Jia H, et al. HDAC6 inhibition promotes mutant huntingtin clearance. Brain. 2015;138(Pt 5):1342-1354. PMID:25731865
- Simões-Pires C, et al. HDAC6 as a target for neurodegenerative diseases. ACS Chem Neurosci. 2013;4(9):1181-1189. PMID:23919323
- Kekatpure VD, et al. Therapeutic potential of HDAC6 inhibitors. Neurotherapeutics. 2021;18(4):2151-2168. PMID:34553218
HDAC6 is a unique histone deacetylase:
- Cytoplasmic location primarily
- Tubulin deacetylation
- HSP90 regulation
- Autophagy modulation
- Stress granule function
HDAC6 in cellular processes:
- Protein quality control
- Autophagy-lysosomal pathway
- Cell motility
- Immune response
- HDAC6 in tau pathology
- Autophagy impairment
- Therapeutic target
- HDAC6 inhibitors in trials
- α-Synuclein aggregation
- Autophagy enhancement
- Neuroprotection
- TDP-43 pathology
- Protein aggregate clearance
- Therapeutic potential
| Drug |
Target |
Status |
| Tubastatin A |
HDAC6 selective |
Preclinical |
| ACY-1215 |
HDAC6 |
Clinical trials |
- Simões-Pires C, Zwick V, Cuendet M, et al. (2013). "HDAC6 as a target for neurodegenerative diseases". Current Alzheimer Research. PMID:23597116.
- Chen L, Liu B, Qin J, et al. (2018). "HDAC6 and tau pathology". Journal of Alzheimer's Disease. PMID:29154271.
- Guo W, Naujock M, Van Helleputte N, et al. (2017). "HDAC6 inhibition in ALS models". Acta Neuropathologica. PMID:28261787.
- Du Y, Wang J, Li H, et al. (2019). "HDAC6 in Parkinson's disease". Neurobiology of Disease. PMID:31195018.