Histone Deacetylase 6 Associated With Selected Behavioral Deficits In Mouse Model For Huntington’s Disease

In a recently published paper in the Brain and Behavior journal entitled “Genetic deletion of the Histone Deacetylase 6 exacerbates selected behavioral deficits in the R6/1 mouse model for Huntington’s disease“, French CNRS researchers in collaboration with institutions from Gottingen in Germany, investigated the role of histone deacetylase 6 (HDAC6) inhibition in Huntington’s disease (HD) and whether it could be used as a therapeutic target.

Huntington’s disease is fatal hereditary neurodegenerative disorder that damages brain motor nerve cells. In the US, an average of 20,000 to 200,000 individuals are affected by the disease and it prevalence worldwide is of about 5–10 cases per 100,000 people. It is believed HD is caused by genetic mutations that result in the production of an altered form of a protein named mutant Huntingtin (mHtt). However, the exact mechanisms related to neurological dysfunctions are still under investigation. Patients with HD suffer from a variety of symptoms including lack of coordination, slowed eye movements, sleep disturbances, seizures, memory deficit, as well as difficulties in chewing, speaking and swallowing. The onset, progression and extent of the symptoms significantly vary between individuals, which often appear in midlife and progressively increase in severity and ultimately lead to death.

There is no available cure for HD, but the symptoms could be relieved by means of physical therapy, talk therapy and medications. Among the several drug approaches, histone deacetylases (HDAC), an enzyme that plays a critical role in developmental events, transcriptional regulation and cell cycle progression, have emerged as potential therapeutic targets for HD, especially in in vitro studies. However, some in vivo studies failed to demonstrate the beneficial effects of HDAC on behavioral HD. To clarify the issue, researchers tested whether reduction or deletion of HDAC6 could correct early cognitive and psychiatric behavior in transgenic mice suffering from HD-like syndrome. Experimentally, this was assessed by evaluating parameters such as weight and clasping, spatial recognition, social behavior, and nesting behavior, which have been shown to be impaired in mouse models of neurodegenerative diseases.

The results suggested that genetic deletion of HDAC6 yielded no decrease in weight loss or deficiency in cognitive abilities and nest-building behavior when compared to previous observations. However, mice suffered from worsen social impairments, reduced spatial recognition and decreased ultrasonic vocalizations. Contrary to what is believed, these findings unfortunately weakened the validity of HDAC6 reduction as a potential therapeutic strategy for HD. These unexpected effects could be explained in terms of additional cellular consequences and anatomical specificity of HDAC6. On the other hand, these data demonstrated that HDAC6 has an important role in the emergence of social HD-like deficits which need further investigation.

In the future, the team plans to clarify the molecular mechanisms underlying the role of HDAC in HD pathophysiology. This could be performed by studying involvement of time or tissue-specific components of HDAC6 or intracerebral injections of a new generation of HDAC6 inhibitors.