HDAC6 inhibitors protect against neuronal damage and have therapeutic potential in neurology and oncology

February 8, 2018, VIB (the Flanders Institute for Biotechnology)

Inhibiting HDAC6 improves the structural stability of cells and protects against neuronal damage. Leuven research uncovered that targeting this mechanism could be a promising therapeutic approach for peripheral neuropathies, whether due to Charcot-Marie-Tooth disease (CMT) or as a side effect of chemotherapy.

Histone deacetylase 6, HDAC6 in short, deacetylates α-tubulin, one of the main structural components of the cytoskeleton. Tubulin is a building block for the cellular tracks that guide the delivery of cargoes, such as mitochondria and vesicles, across the cell. These building blocks can be modified chemically, for example by acetylation, to allow for further fine-tuning of the cytoskeletal stability. This is important, especially in the long axons of human motor neurons and sensory neurons.

Researchers in the lab of prof. Ludo Van Den Bosch (VIB-KU Leuven) previously identified HDAC6 as an interesting target in a for one of the forms of the neurological disorder Charcot-Marie-Tooth disease (CMT). But Van Den Bosch is optimistic that HDAC6 inhibitors could play a much broader role: "Our new findings point to possible therapeutic applications for other forms of CMT, as well as for the neuronal side effects caused by chemotherapy."

"Charcot-Marie-Tooth disease can be caused by more than 80 different mutations, which has made it very difficult to pinpoint a central disease mechanism," explains Dr. Veronick Benoy from the team of Van Den Bosch. She found that of HDAC6 improved both the motor and sensory deficits in another genetic mouse model of CMT. "These results suggest that disturbed acetylation of α-tubulin may be a common hallmark of different forms of CMT. Moreover, we found a cellular link between HDAC6 and the disease-associated protein, indicating that HDAC6 could be linked to CMT disease pathogenesis and that selective inhibition of HDAC6 with a drug could be a beneficial treatment strategy for a wide variety of CMT patients."

But CMT patients are not the only ones who could benefit from HDAC6 inhibitor treatment. Lawrence van Helleputte, also from the Van Den Bosch team, studied the effects of HDAC6 inhibition in a model for chemotherapy-induced . "As a side effect of chemotherapy, many patients develop which can be extremely painful. The fact that cancer is more and more becoming a chronic disease is good news of course, but it also means that we urgently need better options to deal with side effects of the treatments."

Van Helleputte studied the role of HDAC6 in neuropathies caused by vincristine, a very potent anti-cancer drug, which exerts its effect by blocking the assembly of α-tubulin chains in the cytoskeleton. Selective inhibition of HDAC6 did not only prevent axonal damage, it also reduced tumor progression in a leukemia mouse model. Thus, HDAC6 inhibition both protected against neurotoxicity and had additional benefits as an anti-cancer drug. Van Helleputte: "The development of a painful peripheral neuropathy is the dose-limiting side effect of a variety of anti-cancer therapies. HDAC6 inhibitors could drastically improve treatment options."

Van Den Bosch believes studying the molecular mechanisms of disease processes is crucial: "It pays to go beyond compound screening of therapeutic modulators and investigate how exactly a given molecule exerts its effect. Our current results are the perfect example of a situation in which we were able to discover new potential therapeutic targets based on common mechanisms in seemingly different diseases and contexts."

Explore further: Resolving traffic jams in human ALS motor neurons

More information: Lawrence Van Helleputte et al. The role of histone deacetylase 6 (HDAC6) in neurodegeneration, Research and Reports in Biology (2014). DOI: 10.2147/RRB.S35470

Veronick Benoy et al. HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease, Brain (2017). DOI: 10.1093/brain/awx375

Related Stories

Resolving traffic jams in human ALS motor neurons

October 17, 2017
A team of researchers at VIB and KU Leuven used stem cell technology to generate motor neurons from ALS patients carrying mutations in FUS. They found disturbed axonal transport in these motor neurons, but also identified ...

Mice point to a therapy for Charcot-Marie-Tooth disease

August 2, 2011
VIB researchers have developed a mouse model for Charcot-Marie-Tooth (CMT) neuropathy, a hereditary disease of the peripheral nervous system. They also found a potential therapy for this incurable disease. The treatment ...

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Over-activity of enzyme HDAC6 exacerbates symptoms of Amyotrophic Lateral Sclerosis

June 26, 2014
Scientists at VIB and KU Leuven have demonstrated in fruit-flies that over-activity of the enzyme HDAC6 in the nerve ends exacerbates the symptoms of the neurodegenerative condition Amyotrophic Lateral Sclerosis (ALS / Lou ...

Discovery could turn the tables on influenza virus

September 12, 2014
(Medical Xpress)—University of Otago virologist Dr Matloob Husain has identified a potential new weapon in the battle against the flu.

Recommended for you

Fully reprogrammed virus offers new hope as cancer treatment

May 25, 2018
A cancer treatment that can completely destroy cancer cells without affecting healthy cells could soon be a possibility, thanks to research led by Cardiff University.

Research could help fine-tune cancer treatment

May 25, 2018
Cancer therapies that cut off blood supply to a tumour could be more effective in combination with existing chemotherapeutic drugs—according to new research from the University of East Anglia.

Increasing physical activity linked to better immunity in breast cancer patients, study finds

May 25, 2018
A new study from the University of Toronto's Faculty of Kinesiology & Physical Education has found that moderate to vigorous physical activity may help regulate the levels of C-reactive protein – an important biomarker ...

Low-fat diet tied to better breast cancer survival

May 24, 2018
(HealthDay)—Breast cancer patients who adopted a low-fat diet were more likely to survive for at least a decade after diagnosis, compared to patients who ate fattier fare, new research shows.

A cascade of immune processes offers insights to triple-negative breast cancer

May 24, 2018
Cancer is crafty. To survive and thrive, tumors find a way of thwarting our body's natural systems.

By forming clots in tumors, immune cell aids lung cancer's spread

May 24, 2018
University of North Carolina Lineberger Comprehensive Cancer Center researchers have found that by helping to form clots within tumors, immune cells that flock to a particular type of lung cancer are actually building a foundation ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.