The role of histone deacetylase 6 (HDAC6) in neurodegeneration

Abstract

HDAC6 is an enzyme that regulates a variety of biological pathways in dividing cells, but also in post-mitotic neurons. In these cells, different cellular functions and survival are dependent on HDAC6-mediated processes such as intracellular trafficking, antioxidation, chaperone-mediated stress responses, and protein degradation. As a consequence, the interest in HDAC6 as a potential target to treat several neurodegenerative disorders has grown significantly over the last decade. This review summarizes the current knowledge on the interaction partners and functions of HDAC6 as well as the most important arguments for its involvement in several neurodegenerative diseases. As many of these disorders are hallmarked by alterations in HDAC6-mediated pathways, it is hypothesized that HDAC6 could play a pivotal role in the pathophysiology of neurodegeneration. HDAC6-dependent deacetylation of its substrates could result in neurotoxicity, while the ubiquitin-dependent functions of HDAC6 could be essential for neuroprotection. Therefore, targeting the deacetylating activity of HDAC6, while leaving its other functions unhampered, might be an interesting strategy to treat neurodegenerative disorders.

Modulation of Actin network and Tau phosphorylation by HDAC6 ZnF UBP domain

“…The poly-ubiquitinated aggregates are carried via dynein motor to MTOC in order to form aggresomes. The sequestered aggregates in the form of aggresomes are cleared up by autophagy pathway [64,65].…”

Radiosynthesis and preliminary evaluation of an18F‐labeled tubastatin A analog for PET imaging of histone deacetylase 6

“…3 HDAC6, which belongs to the class IIb, is a unique member because of its characteristic localization and functions. 14,15 Deacetylation of α-tubulin in microtubules increases cell motility and enhances cancer cell metastasis and invasion. 12 HDAC6 also has two catalytic domains with different substrate specificities 13 and catalyzes the deacetylation of nonhistone proteins such as α-tubulin, HSP90, cortactin, and the microtubuleassociated protein tau.…”

“…14,15 Deacetylation of α-tubulin in microtubules increases cell motility and enhances cancer cell metastasis and invasion. 20,21 These characteristics of HDAC6 have spurred interest in targeting it with therapeutics for cancers and neurodegenerative diseases, 14,22 with several clinical trials of selective HDAC6 inhibitors for cancers having been performed. 18,19 HDAC6 also has a binding domain against the cytoskeletal motor protein dynein and couples ubiquitinated proteins to dynein motors, thereby mediating their transport along microtubules to aggresomes.…”

“…12 HDAC6 also has two catalytic domains with different substrate specificities 13 and catalyzes the deacetylation of nonhistone proteins such as α-tubulin, HSP90, cortactin, and the microtubuleassociated protein tau. 14,15 Deacetylation of α-tubulin in microtubules increases cell motility and enhances cancer cell metastasis and invasion. 16,17 Additionally, HDAC6 has an ubiquitin binding domain and is involved in the degradation of misfolded and ubiquitinated proteins.…”

“…18,19 HDAC6 also has a binding domain against the cytoskeletal motor protein dynein and couples ubiquitinated proteins to dynein motors, thereby mediating their transport along microtubules to aggresomes. 20,21 These characteristics of HDAC6 have spurred interest in targeting it with therapeutics for cancers and neurodegenerative diseases, 14,22 with several clinical trials of selective HDAC6 inhibitors for cancers having been performed. 23 In the past decade, a number of radiolabeled HDAC ligands for positron emission tomography (PET) imaging have been developed.…”