Yoon Cho, Aliénior Ragot in Brain Behavior

Genetic deletion of the Histone Deacetylase 6 exacerbates selected behavioral deficits in the R6/1 mouse model for Huntington’s disease.
Ragot A, Pietropaolo S, Vincent J, Delage P, Zhang H, Allinquant B, Leinekugel X, Fischer A, Cho YH.
Brain Behav. 2015 Sep;5(9):e00361. doi: 10.1002/brb3.361. Epub 2015 Jun 24.

 

Yoon CHO: Epigenetic approach has emerged as potential therapeutic targets to treat neurodegenerative diseases including hereditary Huntington’s disease (HD). More precisely for HD, inhibitors of histone deacetylases 6 (HDAC6) has attracted attention as this enhances the activity of alpha-tubulin, which is important for vesicular transport of notably brain-derived neurotrophic factor (BDNF).

It is hypothesized that early deficits of cortical BNDF transport to the striatum necessary for striatal neuron protection and survival may account for precocious striatal degeneration in HD. We tested if the reduction of HDAC 6 would be beneficial, and alleviate cognitive and behavioral deficits in our R6/1 transgenic HD mice. While some experiments that reduce HDAC6 produced symptomatic improvement in Parkinson’s disease, Alzheimer’s disease or amyotrophic lateral sclerosis, unfortunately, this was not the case for HD.

To the contrary, the reduction of HDAC6 specifically worsened social behavioral impairments without changing other behavioral phenotypes in our HD mice, even though the BDNF levels in the striatum were greatly increased by the genetic deletion.

Our results may go against the potential therapeutic impact of HDAC6 modulation for HD, but demonstrate a specific role of HDAC6 in the emergence of social HD-like deficits that requires further investigation.
Other effects of the HDAC6 reduction, for example, on the accumulation of ubiquitinated proteins, have significantly contributed to the complex phenotypes that we observed. HDAC6 expressed in the amygdala, hippocampus, locus coeruleus in addition to the striatum and cortex all important for social behaviors, may have contributed to the social behavioral changes in R6/1 mice.

Yoon H Cho / Team leader: Neurobiology of behavior / INCIA /

1st author