HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease

Benoy, Veronick; Helleputte, Lawrence Van; Prior, Robert; d’Ydewalle, Constantin; Haeck, Wanda; Geens, Natasja; Scheveneels, Wendy; Schevenels, Begga; Cader, M Z; Talbot, Kevin; Kozikowski, Alan P.; Berghe, Pieter Vanden; Damme, Philip Van; Robberecht, Wim; Bosch, Ludo Van Den

doi:10.1093/brain/awx375

Cited by 111 publications

(129 citation statements)

References 54 publications

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“…Deficits in axonal transport contribute to many different genetic neuropathies (Prior et al, 2017;Beijer et al, 2019), and its early involvement in disease may be a common driver in peripheral nerve selectivity typical of many forms of CMT2. Indeed, disruption of long-range trafficking has been identified in sensory neurons cultured from CMT2D DRG (Benoy et al, 2018;Mo et al, 2018). Contrastingly, we found no difference in retrograde transport of signalling endosomes between wild-type and Gars C201R/+ at one and three months of age (Figure 4 and Supplementary Figure S3).…”

Section: Long-range Transport Is Not Universally Impaired In Cmt2d Sementioning

confidence: 64%

“…Pre-symptomatic disturbances in axonal trafficking are thought to underlie, or at least contribute to, several neurological diseases (Sleigh et al, 2019). Indeed, primary DRG neurons cultured from 12 day old Gars Nmf249/+ mice display reduced retrograde transport speeds of nerve growth factor (NGF)-loaded endosomes (Mo et al, 2018), while reduced mitochondrial motility was also identified in sensory processes of 12 month old Gars C201R/+ mice (Benoy et al, 2018). Disruption of two different cargoes suggests a broad transport impairment (e.g.…”

Section: Long-range Signalling Endosome Transport Is Unaffected In CMmentioning

confidence: 99%

“…While some of these misinteractions are with neuronally-enriched proteins, the pathomechanisms underlying neuronal selectivity in CMT2D remain unresolved. Nevertheless, several recent studies indicate that impairments in the processes of axonal transport (Benoy et al, 2018;Mo et al, 2018) and protein translation (Niehues et al, 2015) may be playing a causative role.…”

Section: Introductionmentioning

confidence: 99%

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Altered sensory neuron development in CMT2D mice is site-specific and linked to increased GlyRS levels

Sleigh

Mech

Aktar

et al. 2020

Preprint

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Dominant, missense mutations in the widely and constitutively expressed GARS1 gene cause a peripheral neuropathy that usually begins in adolescence and principally impacts the upper limbs. Caused by a toxic gain-of-function in the encoded glycyl-tRNA synthetase (GlyRS) enzyme, the neuropathology appears to be independent of the canonical role of GlyRS in aminoacylation. Patients display progressive, life-long weakness and wasting of muscles in hands followed by feet, with frequently associated deficits in sensation. When dysfunction is observed in motor and sensory nerves, there is a diagnosis of Charcot-Marie-Tooth disease type 2D (CMT2D), or distal hereditary motor neuropathy type V if the symptoms are purely motor. The cause of this varied sensory involvement remains unresolved, as are the pathomechanisms underlying the selective neurodegeneration characteristic of the disease. We have previously identified in CMT2D mice that neuropathy-causing Gars mutations perturb sensory neuron fate and permit mutant GlyRS to aberrantly interact with neurotrophin receptors (Trks). Here, we extend this work by interrogating further the anatomy and function of the CMT2D sensory nervous system in mutant Gars mice, obtaining several key results: 1) sensory pathology is restricted to neurons innervating the hindlimbs; 2) perturbation of sensory development is not common in mouse models of neuromuscular disease; 3) in vitro axonal transport of signalling endosomes is not impaired in afferent neurons of all CMT2D mouse models; and 4) Gars expression is selectively elevated in a subset of sensory neurons and linked to sensory developmental defects. These findings highlight the importance of comparative neurological assessment in mouse models of disease and shed light on key proposed neuropathogenic mechanisms in GARS1-linked neuropathy.

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Section: Long-range Transport Is Not Universally Impaired In Cmt2d Sementioning

confidence: 64%

Section: Long-range Signalling Endosome Transport Is Unaffected In CMmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Altered sensory neuron development in CMT2D mice is site-specific and linked to increased GlyRS levels

Sleigh

Mech

Aktar

et al. 2020

Preprint

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“…Currently, two genetics experiments in flies and mice have demonstrated that dominant mutations in GARS cause CMT through toxic gain-of-function effects [10,18]. Several binding partner of CMT mutants have been discovered, including Nrp1 [25], Trk [26] and HDAC6 [27,28]. Here we presented that SIRT2, the acetylated tubulin deacetylase, is able to bind tightly with wildtype GARS comparing with CMT mutants, we didn't rule out the possibility that CMT mutants might gain the functions to increase deacetylation activity of SIRT2 which leading to decrease the acetylated tubulin.…”

Section: Disscussionmentioning

confidence: 99%

SIRT2-knockdown Rescues GARS-induced Charcot-Marie-Tooth Neuropathy

Shen

Qin

et al. 2019

Preprint

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Charcot-Marie-Tooth disease is the most common inherited peripheral neuropathy. Dominant mutations in glycyl-tRNA synthetase (GARS) gene cause peripheral nerve degeneration and lead to CMT disease type 2D. Mutations in GARS (GARS CMT2D ) show partial loss-of-function features, suggesting that tRNA-charging deficits play a role in disease pathogenesis, but the underlying mechanisms are not fully understood. In this study we report that wild-type GARS tightly binds the NAD + -dependent deacetylase SIRT2 and inhibits its deacetylation activity, resulting in the hyperacetylated -tubulin, the major substrate of SIRT2. Previous studies showed that acetylation of-tubulin protects microtubules from mechanical breakage and keep axonal transportation. However, CMT2D mutations in GARS can not inhibit SIRT2 deacetylation, which leads to decrease acetylated -tubulin and severe axonal transport deficits. Genetic reduction of SIRT2 in the Drosophila model rescues the GARS-induced axonal CMT neuropathy and extends the life span. Our findings demonstrate the pathogenic role of SIRT2-dependent -tubulin deacetylation in mutant GARS-induced neuropathies and provide new perspectives for targeting SIRT2 as a potential therapy against hereditary axonopathies.

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“…Therefore, mutations that weaken INF2 binding to the CAP/KAc-actin inhibitory complex may lead to disease through increased INF2 activity. Interestingly, recent studies have shown that aberrant HDAC6 activity can also lead to CMTD [75][76][77] , raising the possibility of another route for INF2 activation in this disease. Overall, our study provides a framework for understanding both actin regulation and disease progression in a new way.…”

Section: Inf2 Regulation and Human Diseasementioning

confidence: 99%

A complex containing lysine-acetylated actin inhibits the formin INF2

Fung

Kettenbach

et al. 2018

Preprint

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INF2 is a member of the formin family of actin assembly factors. Dominant mis-sense mutations in INF2 link to two diseases: focal segmental glomerulosclerosis (FSGS), a kidney disease; and Charcot-Marie-Tooth disease (CMTD), a neuropathy. All disease mutations map to the autoinhibitory Diaphanous Inhibitory Domain (DID). Curiously, purified INF2 is not autoinhibited, suggesting the existence of additional cellular inhibitors. We purified an INF2 inhibitor from mouse brain, and identified it as a complex between lysine-acetylated actin (KAc-actin) and cyclase-associated protein (CAP). Inhibition of INF2 by CAP/KAc-actin requires INF2 DID. Treatment of CAP/KAc-actin with histone deacetylase 6 (HDAC6) releases INF2 inhibition, while HDAC6 inhibitors block cellular INF2 activation. INF2 disease mutants are poorly inhibited by CAP/KAc-actin, suggesting that FSGS and CMTD result from reduced CAP/KAc-actin binding. This is the first demonstrated role for lysine-acetylated actin: regulation of an actin assembly factor by a novel mechanism, which we call facilitated auto-inhibition.

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HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease

Cited by 111 publications

References 54 publications

Altered sensory neuron development in CMT2D mice is site-specific and linked to increased GlyRS levels

Altered sensory neuron development in CMT2D mice is site-specific and linked to increased GlyRS levels

SIRT2-knockdown Rescues GARS-induced Charcot-Marie-Tooth Neuropathy

A complex containing lysine-acetylated actin inhibits the formin INF2

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