HDAC6 Summary

HDAC6 is a protein deacetylase that catalyzes the removal of acetyl groups from a broad spectrum of non-histone substrates (UniProt: Q9UBN7). It plays central roles in microtubule dynamics through α-tubulin deacetylation, autophagy regulation via deacetylation of CTTN and SQSTM1, and protein quality control by directing misfolded proteins to aggresomes for clearance. HDAC6 also modulates DNA repair, mitochondrial transport, and transcriptional regulation through deacetylation of target proteins including MLH1, RHOT1, and SP1.

HDAC6 is broadly expressed and functions in the cytoplasm and nucleus across multiple cellular compartments. UniProt documents an association with chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia (CDP-PBHM; MIM 300863), though this is a rare genetic condition distinct from neurodegenerative disease.

In Alzheimer's disease, HDAC6 is significantly upregulated in post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics), with a mean log2 fold-change of +0.45 across subcellular fractions. This elevation may reflect altered protein quality control responses or changes in cytoskeletal dynamics characteristic of AD pathology.