HDAC6 α-tubulin deacetylase: A potential therapeutic target in neurodegenerative diseases

Li, Guoyi; Jiang, Hao-Bo; Chen, Ming; Xie, Hongrong; Hu, Linsen

doi:10.1016/j.jns.2011.02.017

Cited by 124 publications

(86 citation statements)

References 103 publications

(190 reference statements)

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“…The ubiquitin-binding activity of HDAC6 is critical for its function in the transport of ubiquitinated proteins to aggresomes, thereby facilitating cellular adaptive responses to the accumulation of misfolded proteins (70). Consistently, we observed that the binding of HDAC6 to ubiquitinated proteins increases upon CS exposure.…”

Section: Figure 10supporting

confidence: 83%

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Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

et al. 2013

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Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) that are associated with epithelial cell dysfunction, cilia shortening, and mucociliary clearance disruption. Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells (MTECs). Autophagy-impaired (Becn1 +/-or Map1lc3B -/-) mice and MTECs resisted CS-induced cilia shortening. Furthermore, CS increased the autophagic turnover of ciliary proteins, indicating that autophagy may regulate cilia homeostasis. We identified cytosolic deacetylase HDAC6 as a critical regulator of autophagy-mediated cilia shortening during CS exposure. Mice bearing an X chromosome deletion of Hdac6 (Hdac6 -/Y ) and MTECs from these mice had reduced autophagy and were protected from CS-induced cilia shortening. Autophagy-impaired Becn1 -/-, Map1lc3B -/-, and Hdac6 -/Y mice or mice injected with an HDAC6 inhibitor were protected from CS-induced mucociliary clearance (MCC) disruption. MCC was preserved in mice given the chemical chaperone 4-phenylbutyric acid, but was disrupted in mice lacking the transcription factor NRF2, suggesting that oxidative stress and altered proteostasis contribute to the disruption of MCC. Analysis of human COPD specimens revealed epigenetic deregulation of HDAC6 by hypomethylation and increased protein expression in the airways. We conclude that an autophagy-dependent pathway regulates cilia length during CS exposure and has potential as a therapeutic target for COPD.

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Section: Figure 10supporting

confidence: 83%

“…HDAC6 has dual functionality as a ubiquitin-binding protein and as a regulator of protein acetylation (70). The ubiquitin-binding activity of HDAC6 is critical for its function in the transport of ubiquitinated proteins to aggresomes, thereby facilitating cellular adaptive responses to the accumulation of misfolded proteins (70).…”

Section: Figure 10mentioning

confidence: 99%

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

et al. 2013

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“…10 Selective inhibition of HDAC6 by small molecules promotes survival and regrowth of neurons following injury, and HDAC6 inhibition thus holds promise for the treatment of spinal cord injury, depression, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. 11,12 Moreover, selective inhibition of HDAC6 does not lead to serious toxicity as has been observed with inhibition of the class I isoforms, making it a presumably a safer drug target. 13 Currently, four HDACIs have been approved by the FDA, including suberoylanilide hydroxamic acid (Vorinostat), FK228 (Romidepsin), LBH-589 (Panobinostat), and PXD101 (Belinostat).…”

mentioning

confidence: 99%

Design and Synthesis of Mercaptoacetamides as Potent, Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors

Zhang

Bařinka

et al. 2017

ACS Med. Chem. Lett.

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A series of nonhydroxamate HDAC6 inhibitors were prepared in our effort to develop potent and selective compounds for possible use in central nervous system (CNS) disorders, thus obviating the genotoxicity often associated with the hydroxamates. Halogens are incorporated in the cap groups of the designed mercaptoacetamides in order to increase brain accessibility. The indole analogue 7e and quinoline analogue 13a displayed potent HDAC6 inhibitory activity (IC 50 , 11 and 2.8 nM) and excellent selectivity against HDAC1. Both 7e and 13a together with their ester prodrug 14 and disulfide prodrugs 15 and 16 were found to be effective in promoting tubulin acetylation in HEK cells. The disulfide prodrugs 15 and 16 also released a stable concentration of 7e and 13a upon microsomal incubation. Administration of 15 and 16 in vivo was found to trigger an increase of tubulin acetylation in mouse cortex. These results suggest that further exploration of these compounds for the treatment of CNS disorders is warranted.

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“…HDAC6 is mainly localized in the cytosol, and many activities of HDAC6 are exerted through its modulatory effects on cytoskeletal proteins (for recent reviews see, Boyault et al, 2007;Li et al, 2011;Richter-Landsberg and Leyk, 2013). HDAC6 deacetylates substrates other than histones, in particular α-tubulin, cortactin and HSP90.…”

Section: Tau Acetylation and The Role Of Hdac6mentioning

confidence: 99%

Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration

Richter‐Landsberg¹

2016

Biological Chemistry

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Abstract:Oligodendrocytes are dependent on an intact, dynamic microtubule (MT) network, which participates in the elaboration and stabilization of myelin forming extensions, and is essential for cellular sorting processes. The microtubule-associated protein tau is constituent of oligodendrocytes. During culture maturation it is developmentally regulated and important for MT stability, MT formation and intracellular trafficking. Downregulation of tau impairs process outgrowth and the transport of myelin basic protein (MBP) mRNA to the cell periphery. Cells fail to differentiate into MBP-expressing, sheet-forming oligodendrocytes. Tau-positive inclusions originating in oligodendrocytes and white matter pathology are prominent in frontotemporal dementias, such as Pick's disease, progressive supranuclear palsy and corticobasal degeneration. An impairment or overload of the proteolytic degradation systems, i.e. the ubiquitin proteasomal system and the lysosomal degradation pathway, has been connected to the formation of protein aggregates. Large protein aggregates are excluded from the proteasome and degraded by autophagy, which is a highly selective process and requires receptor proteins for ubiquitinated proteins, including histone deacetylase 6 (HDAC6). HDAC6 is present in oligodendrocytes, and α-tubulin and tau are substrates of HDAC6. In this review our current knowledge of the role of tau and protein aggregate formation in oligodendrocyte cell culture systems is summarized.

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HDAC6 α-tubulin deacetylase: A potential therapeutic target in neurodegenerative diseases

Cited by 124 publications

References 103 publications

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

Design and Synthesis of Mercaptoacetamides as Potent, Selective, and Brain Permeable Histone Deacetylase 6 Inhibitors

Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration

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