The HDAC6 gene (Histone Deacetylase 6) encodes a unique class IIb histone deacetylase that is primarily localized in the cytoplasm. Unlike other HDACs, HDAC6 predominantly targets non-histone proteins including α-tubulin, Hsp90, and cortactin, making it a critical regulator of protein quality control, aggresome formation, and autophagic clearance of misfolded proteins[1].
HDAC6 has emerged as a promising therapeutic target in neurodegenerative diseases due to its central role in protein homeostasis. The enzyme is uniquely positioned to modulate multiple degradation pathways including autophagy, proteasome function, and aggresome clearance. This makes HDAC6 particularly relevant to diseases characterized by protein aggregate accumulation, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and ALS[2].
The discovery that HDAC6 knockout mice are viable and resistant to certain proteotoxic challenges has further highlighted its potential as a drug target. Selective HDAC6 inhibitors have shown neuroprotective effects in multiple disease models, and several compounds have entered clinical trials for neurological indications.
| Attribute | Value |
|---|---|
| Symbol | HDAC6 |
| Full Name | Histone Deacetylase 6 |
| Chromosomal Location | Xp11.23 |
| NCBI Gene ID | 10013 |
| OMIM | 300231 |
| Ensembl ID | ENSG00000094631 |
| UniProt ID | Q9UQR8 |
| Protein Size | 1215 amino acids |
| Molecular Weight | ~131 kDa |
| Expression | Ubiquitous, highest in brain, liver, kidney |
HDAC6 contains two catalytic domains and a zinc-finger ubiquitin-binding domain[3]:
| Domain | Function |
|---|---|
| N-terminal catalytic domain | Primary deacetylase activity |
| C-terminal catalytic domain | Secondary deacetylase activity |
| Zinc-finger domain | Binds ubiquitin, facilitates aggregate clearance |
The two catalytic domains are functionally independent, allowing HDAC6 to deacetylate multiple substrates simultaneously. The ubiquitin-binding domain specifically recognizes ubiquitinated proteins, targeting them for autophagic degradation.
HDAC6 differs from other HDACs in its substrate specificity[4]:
| Substrate | Function | Effect of Deacetylation |
|---|---|---|
| α-Tubulin | Microtubule stability | Increased acetylation, enhanced transport |
| Hsp90 | Molecular chaperone | Activation, protein folding |
| Cortactin | Actin dynamics | Remodeling, cell motility |
| Periostin | Extracellular matrix | Unknown in brain |
| SOD1 | Antioxidant enzyme | Increased stability |
HDAC6 is a central player in cellular protein quality control[5]:
Through tubulin deacetylation, HDAC6 regulates[6]:
HDAC6 participates in cellular stress responses[7]:
HDAC6 contributes to AD pathogenesis through multiple mechanisms[4:1]:
HDAC6 is implicated in PD through α-synuclein processing[8]:
In HD, HDAC6 modulates mutant huntingtin clearance[9]:
HDAC6 plays complex roles in ALS[10]:
| Compound | Selectivity | Status | Notes |
|---|---|---|---|
| Tubastatin A | HDAC6-selective | Research | First selective inhibitor |
| ACY-1215 (Ricolinostat) | HDAC6-selective | Phase I/II | Clinical trials for cancer |
| Nextceastin A | HDAC6-selective | Preclinical | Improved brain penetration |
| CHAP-1 | HDAC6-selective | Research | Cyclic peptide |
Targeting HDAC6 offers several approaches[11]:
Developing HDAC6 therapies faces challenges:
HDAC6 is expressed in various brain regions:
HDAC6 localizes to:
HDAC6 modulates autophagy through multiple mechanisms[12]:
The aggresome-autophagy pathway involves HDAC6[3:1]:
Misfolded proteins → Ubiquitination → HDAC6 binding → Transport to aggresome
↓
Autophagy recruitment → Lysosomal degradation
HDAC6 affects mitochondrial health[13]:
HDAC6 activity may serve as a biomarker[14]:
Simoes-Pires C, et al. HDAC6 as a therapeutic target in neurodegenerative diseases. Curr Alzheimer Res. 2013. ↩︎
Yan J, et al. HDAC6 regulates neuronal viability and susceptibility to Parkinson's disease. J Neurochem. 2013. ↩︎
Liu Y, et al. HDAC6 and aggresome formation. Cell. 2014. ↩︎ ↩︎
Li Y, et al. HDAC6 and tau acetylation in Alzheimer's disease. Nat Rev Neurosci. 2018. ↩︎ ↩︎
Brandherm I, et al. HDAC6 and autophagy in neurodegeneration. Acta Neuropathol. 2020. ↩︎
Liu H, et al. HDAC6 and microtubule acetylation. J Neurosci. 2017. ↩︎
Park SY, et al. HDAC6 and stress granules. Cell Mol Neurobiol. 2016. ↩︎
Ren Y, et al. HDAC6 and alpha-synuclein aggregation. J Biol Chem. 2019. ↩︎
Duan W, et al. Targeting HDAC6 for Huntington's disease. Expert Opin Ther Targets. 2013. ↩︎
Guo W, et al. HDAC6 and protein aggregates in ALS. Nat Neurosci. 2016. ↩︎
Fischer MJ, et al. HDAC6 inhibitors for neuroprotection. J Med Chem. 2017. ↩︎
Kim SH, et al. HDAC6 and autophagy induction. Autophagy. 2019. ↩︎
Cheng Y, et al. HDAC6 and mitochondrial function. Cell Death Dis. 2018. ↩︎
Zhao X, et al. HDAC6 as biomarker in neurodegeneration. Neurology. 2018. ↩︎