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ACS Chem Neurosci. 2020 Jan 8. doi: 10.1021/acschemneuro.9b00338. [Epub ahead of print]

Novel HDAC6 Inhibitors Increase Tubulin Acetylation and Rescue Axonal Transport of Mitochondria in a Model of Charcot-Marie-Tooth Type 2F.

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John van Geest Centre for Brain Repair, Department of Clinical Neurosciences , University of Cambridge , Forvie Site Robinson Way , Cambridge CB2 0PY , United Kingdom.
Department of Anatomy, Histology and Embryology, Faculty of Medicine , University of Szeged , Szeged H-6724 , Hungary.
Takeda Pharmaceutical Company Limited , 26-1, Muraoka-higashi 2-chome , Fujisawa , Kanagawa 251-8555 , Japan.
Takeda Development Centre Europe Ltd. , 61 Aldwych , London WC2B 4AE , United Kingdom.
Babraham Institute , Babraham, Cambridge CB22 3AT , United Kingdom.


Disruption of axonal transport causes a number of rare, inherited axonopathies and is heavily implicated in a wide range of more common neurodegenerative disorders, many of them age-related. Acetylation of α-tubulin is one important regulatory mechanism, influencing microtubule stability and motor protein attachment. Of several strategies so far used to enhance axonal transport, increasing microtubule acetylation through inhibition of the deacetylase enzyme histone deacetylase 6 (HDAC6) has been one of the most effective. Several inhibitors have been developed and tested in animal and cellular models, but better drug candidates are still needed. Here we report the development and characterization of two highly potent HDAC6 inhibitors, which show low toxicity, promising pharmacokinetic properties, and enhance microtubule acetylation in the nanomolar range. We demonstrate their capacity to rescue axonal transport of mitochondria in a primary neuronal culture model of the inherited axonopathy Charcot-Marie-Tooth Type 2F, caused by a dominantly acting mutation in heat shock protein beta 1.


CMT; HDAC6; axonal transport; axonopathy; mitochondria; α-tubulin

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