Hdac6 Knock-Out Increases Tubulin Acetylation but Does Not Modify Disease Progression in the R6/2 Mouse Model of Huntington's Disease

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC) inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6) in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF) from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD.

HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons

“…Our findings agree, however, with other studies in neurons, where HDAC6 inhibition alleviated abnormal A and tau accumulation [53,64], and with in vivo HDAC6-knockout in R6/2 mice showing no increase in mHtt aggregates [65]. Thus, as previously suggested [65], some of the effects of HDAC6 in cell-lines may not apply to neurons.…”

“…Thus, as previously suggested [65], some of the effects of HDAC6 in cell-lines may not apply to neurons.…”

EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

“…HDAC6 overexpression leads to the complete deacetylation of microtubules, whereas inhibition of HDAC6 by specific inhibitors, RNAi-mediated protein depletion, or genetic knockout increases microtubule acetylation. 26,45,46 Our results revealed that HDAC6 inhibition by tubacin or specific RNAi was able to efficiently rescue the decrease in a-tubulin acetylation induced by silencing EWSR1 in mitotic cells, which suggests the involvement of EWSR1 in microtubule dynamics via HDAC6. However, the molecular mechanisms are not yet explored.…”

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

“…On the other hand, another group showed that genetic depletion of HDAC6 did not modify the progression of Hungtinton's disease 49 . It was also shown that phosphorylation of HDAC6, activating its deacetylase activity, promotes proper aggresome formation and protects from toxicity 50 .…”