Histone Deacetylase 6 in Health and Disease

Seidel, Carole; Schnekenburger, Michaël; Dicato, Mario; Diederich, Marc

doi:10.2217/epi.14.69

Cited by 185 publications

(218 citation statements)

References 118 publications

(139 reference statements)

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“…HDAC6 is the major α-tubulin deacetylase, and its expression is abnormally high in patients with neurodegenerative diseases, including Parkinson’s, amyotrophic lateral sclerosis, and Alzheimer’s, and with cancer and pathological autoimmune responses [78]. In each of our models of IKAP deficiency, we observed increased HDAC6 levels relative to controls (Fig 4A–4D).…”

Section: Resultsmentioning

confidence: 80%

Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia

et al. 2016

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Familial Dysautonomia (FD) is a neurodegenerative disease in which aberrant tissue-specific splicing of IKBKAP exon 20 leads to reduction of IKAP protein levels in neuronal tissues. Here we generated a conditional knockout (CKO) mouse in which exon 20 of IKBKAP is deleted in the nervous system. The CKO FD mice exhibit developmental delays, sensory abnormalities, and less organized dorsal root ganglia (DRGs) with attenuated axons compared to wild-type mice. Furthermore, the CKO FD DRGs show elevated HDAC6 levels, reduced acetylated α-tubulin, unstable microtubules, and impairment of axonal retrograde transport of nerve growth factor (NGF). These abnormalities in DRG properties underlie neuronal degeneration and FD symptoms. Phosphatidylserine treatment decreased HDAC6 levels and thus increased acetylation of α-tubulin. Further PS treatment resulted in recovery of axonal outgrowth and enhanced retrograde axonal transport by decreasing histone deacetylase 6 (HDAC6) levels and thus increasing acetylation of α-tubulin levels. Thus, we have identified the molecular pathway that leads to neurodegeneration in FD and have demonstrated that phosphatidylserine treatment has the potential to slow progression of neurodegeneration.

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Section: Resultsmentioning

confidence: 80%

Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia

et al. 2016

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“…HDAC6-selective inhibitors are currently under investigation in multiple clinical settings, including cancer and neurodegenerative diseases 11, 32-34. Our findings suggest that the side effects of HDAC6 inhibition on immunity should be considered as a part of clinical trials.…”

Section: Discussionmentioning

confidence: 83%

HDAC6 regulates IL-17 expression in T lymphocytes: implications for HDAC6-targeted therapies

Yan¹,

Liu²,

Hong³

et al. 2017

Theranostics

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The pro-inflammatory cytokine interleukin 17 (IL-17) is critically involved in immunity and inflammation. T-helper 17 and γδ T cells are the predominant sources of IL-17 in the immune system. However, the mechanisms by which the expression of IL-17 is regulated in T cells remain elusive. Here, we demonstrate that loss of histone deacetylase 6 (HDAC6) in mice does not affect the generation of CD4+ or CD8+ T cells, but stimulates the development of IL-17-producing γδ T cells. Our data further show that HDAC6 deficiency increases the production of IL-17 by Vγ4+ γδ T cells in the spleen and lymph nodes. Consistent with these observations, small-molecule inhibition of HDAC6 activity in γδ T cells promotes the expression of IL-17 in vitro. These data thus reveal that HDAC6 represses IL-17 production in T cells, providing novel insights into the role of HDAC6 in the immune system. These findings also have important implications for the clinical investigation of HDAC6-targeted therapies.

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“…The abundant expression level of acetylated a-tubulin was also demonstrated in walleye brain and retina extracts. In vertebrates, the addition of acetyl to tubulin is done mainly by a-tubulin acetyltransferase 1 (aTAT1 or also known as mechanosensory protein 17 or MEC-17) (Akella et al 2010), whereas removal is done with a histone deacetylase, HDAC6 (Seidel et al 2015), and/or a sirtuin family member, SIRT2 (Skoge et al 2014). For fish, MEC-17, HDAC6 and SIRT2 have been studied almost exclusively in zebrafish (Akella et al 2010;Kaluza et al 2011;Zhou et al 2014), but these cell lines should allow acetylation/ …”

Section: Discussionmentioning

confidence: 99%

Demonstration of primary cilia and acetylated α-tubulin in fish endothelial, epithelial and fibroblast cell lines

Bols

2015

Fish Physiol Biochem

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Primary cilia (PC) were demonstrated for the first time in fish endothelial, epithelial and fibroblast cell lines through immunofluorescence staining with the monoclonal antibody, 6-11B-1, against acetylated α-tubulin. The study was carried out with eight recently developed cell lines from the walleye, Sander vitreus (Mitchill). These were three fibroblast-like cell lines, WE-cfin11f, WE-skin11f and WE-liver3 from, respectively, the caudal fin, skin and liver, and three epithelial-like cell lines, WE-cfin11e, WE-spleen6 and WErpe from, respectively, the caudal fin, spleen and retina. Also, endothelial-like WEBA from the bulbus arteriosus and glial-like WE-brain5 from the brain were used. Immunocytochemistry revealed strong staining for acetylated α-tubulin in mitotic spindles and midbodies for all cell lines, and in PC for all cell lines except WE-skin11f. Staining of cytoplasmic microtubules (fibrils) was absent in three cell lines, including WEBA, but present in the others, especially WE-skin11f, which might have obscured PC detection in these cells. Tubacin, an inhibitor of histone deacetylase 6, induced cytoplasmic fibrils in WEBA and the intensity of their staining in WE-cfin11f. These results suggest that the cell lines might differ in their deacetylase activities, making them useful for studying this tubulin modification in teleosts, as well as for studying PC.

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Histone Deacetylase 6 in Health and Disease

Cited by 185 publications

References 118 publications

Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia

Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia

HDAC6 regulates IL-17 expression in T lymphocytes: implications for HDAC6-targeted therapies

Demonstration of primary cilia and acetylated α-tubulin in fish endothelial, epithelial and fibroblast cell lines

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