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

Abstract

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 agerelated. 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 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 characterisation 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.

A novel histone deacetylase 6 inhibitor improves myelination of Schwann cells in a model of Charcot–Marie–Tooth disease type 1A

“…The therapeutic potential of HDAC6 inhibition has been well established in CMT2F caused by the defective axonal transport. HDAC6 inhibition has been reported to enhance axonal transport and, thus, improve neuronal function (Adalbert et al, 2020; Benoy et al, 2017, 2018; d'Ydewalle et al, 2011; Mo et al, 2018). However, the therapeutic potential of HDAC6 inhibition has not yet been tested in CMT1A caused by the defective myelination of Schwann cells.…”

“…HDAC6 inhibition has been reported to enhance axonal transport and, thus, improve neuronal function (Adalbert et al, 2020;Benoy et al, 2017Benoy et al, , 2018d'Ydewalle et al, 2011;Mo et al, 2018). (Figure 2b,c).…”

“…The inhibition or deletion of HDAC6 has been reported to reduce the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, chemotherapy‐induced neuropathy, and axonal CMT neuropathy (Dompierre et al, 2007; Govindarajan et al, 2013; Krukowski et al, 2017; Ma et al, 2019; Rossaert & Van Den Bosch, 2020; Selenica et al, 2014; Taes et al, 2013; Van Hellelputte et al, 2018). In CMT type 2F (CMT2F) and CMT type 2D (CMT2D) models, in which defective axonal transport results from reduced microtubule stability, HDAC6 inhibition restored the acetylation of α‐tubulin and axonal transport, restoring peripheral nerve function (Adalbert et al, 2020; Benoy et al, 2017, 2018; d'Ydewalle et al, 2011; Mo et al, 2018). However, the efficacy of HDAC6 inhibition in CMT1, which is a demyelinating neuropathy, has not yet been reported.…”

HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy

“…Dysregulated HDAC6 interactions with mutated MFN2 could lead to mitochondrial deficits that, based on the literature, may be one of many important factors in the development of CMT2A peripheral neuropathy (Baloh et al, 2007;Misko et al, 2010;Picci et al, 2020). Adalbert et al (2020) observed in a mouse model of CMT2F slowed and stunted movement of mitochondria, which was restored after inhibition of HDAC6 (D' Ydewalle et al, 2011). CMT2F is a subtype of CMT2 that is autosomal dominant and involves the heat shock protein family B (HSPB1) gene (Fridman et al, 2015;Bird, 2020).…”

Charcot–Marie–Tooth disease type 2F associated with biallelic HSPB1 mutations

“…Remarkably, in 2011 d'Ydewalle and colleagues discovered that the use of a selective HDAC6 inhibitor successfully reversed the clinical phenotype in HSPB1 S135F rodent models. 36 Further preclinical studies of these compounds in other models of axonal CMT have revealed promising results, 39,40 thereby paving the way for future clinical trials in patients.…”