HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1–induced Charcot-Marie-Tooth disease
TL;DR: An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant H SPB1 mice.
Abstract: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated α-tubulin abundance and induced severe axonal transport deficits. An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of α-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.
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TL;DR: The current state of knowledge about axonal transport defects that might contribute to the pathogenesis of particular neurodegenerative diseases are reviewed.
Abstract: The intracellular transport of organelles along an axon is crucial for the maintenance and function of a neuron. Anterograde axonal transport has a role in supplying proteins and lipids to the distal synapse and mitochondria for local energy requirements, whereas retrograde transport is involved in the clearance of misfolded and aggregated proteins from the axon and the intracellular transport of distal trophic signals to the soma. Axonal transport can be affected by alterations to various components of the transport machinery. Here, we review the current state of knowledge about axonal transport defects that might contribute to the pathogenesis of particular neurodegenerative diseases.
655 citations
TL;DR: This work discusses how tubulin isotypes and post-translational modifications control microtubule behaviour at the molecular level and how this translates into physiological functions at the cellular and organism levels, and shows how fine-tuning of microtubules function by some tubulin modifications can affect homeostasis.
Abstract: Microtubules are core components of the eukaryotic cytoskeleton with essential roles in cell division, shaping, motility and intracellular transport. Despite their functional heterogeneity, microtubules have a highly conserved structure made from almost identical molecular building blocks: the tubulin proteins. Alternative tubulin isotypes and a variety of post-translational modifications control the properties and functions of the microtubule cytoskeleton, a concept known as the 'tubulin code'. Here we review the current understanding of the molecular components of the tubulin code and how they impact microtubule properties and functions. We discuss how tubulin isotypes and post-translational modifications control microtubule behaviour at the molecular level and how this translates into physiological functions at the cellular and organism levels. We then go on to show how fine-tuning of microtubule function by some tubulin modifications can affect homeostasis and how perturbation of this fine-tuning can lead to a range of dysfunctions, many of which are linked to human disease.
379 citations
TL;DR: This Review discusses how NGS is being employed in the diagnostic evaluation of patients with CMT and how the genetic advances in CMT are influencing clinical practice, and explores how genetic advances have broadened the phenotype of C MT and related disorders.
Abstract: Charcot-Marie-Tooth disease (CMT) refers to a group of inherited neuropathies with a broad range of phenotypes, inheritance patterns and causative genes The number of disease genes identified in CMT has expanded rapidly over the past few decades, such that more than 60 CMT-associated genes have now been discovered This rise in genetic discovery can be attributed to the development of next-generation sequencing (NGS) technology, which allows the entire exome or genome to be sequenced in a matter of days In this Review, we discuss how NGS is being employed in the diagnostic evaluation of patients with CMT and how the genetic advances in CMT are influencing clinical practice In particular, we explore how genetic advances have broadened the phenotype of CMT and related disorders and how NGS allows a large number of CMT genes to be screened simultaneously early in the evaluation of an unexplained neuropathy Finally, we discuss the different methods of NGS that can be used in CMT and related disorders, and propose a simple diagnostic algorithm in which clinical assessment and neurophysiology are used to guide the application of phenotype specific 'panels'
287 citations
TL;DR: This review focuses on recent studies that highlight the importance of HDAC6‐mediated biological processes, disease mechanisms and HDAC 6‐selective inhibitors.
Abstract: Histone deacetylase (HDAC) 6 is the best-characterized class IIb deacetylase that regulates many important biological processes via the formation of complexes with its partner proteins. HDAC6 is important both for cytoplasmic and nuclear functions. Unlike other deacetylases, HDAC6 has unique substrate specificity for nonhistone proteins. Such diverse functions of HDAC6 suggest that it serves a potential therapeutic target for the treatment of a wide range of diseases. This therapeutic interest in HDAC6 stems from the observation that HDAC6 may be overexpressed or deregulated in various cancers, neurodegenerative diseases and inflammatory disorders. Despite extensive efforts, however, very few HDAC6-selective inhibitors have been identified and the precise structural determinants remain undefined. Future efforts aiming to better define the structure and function of HDAC6 should provide the basis for the discovery of novel effective inhibitors. In this review, we focus on recent studies that highlight the importance of HDAC6-mediated biological processes, disease mechanisms and HDAC6-selective inhibitors.
265 citations
TL;DR: It is reported that mice lacking HDAC6 are cognitively normal but reducing endogenousHDAC6 levels restores learning and memory and α‐tubulin acetylation in a mouse model for Alzheimer's disease (AD).
Abstract: Histone deacetylases (HDACs) are currently being discussed as promising therapeutic targets to treat neurodegenerative diseases. However, the role of specific HDACs in cognition and neurodegeneration remains poorly understood. Here, we investigate the function of HDAC6, a class II member of the HDAC superfamily, in the adult mouse brain. We report that mice lacking HDAC6 are cognitively normal but reducing endogenous HDAC6 levels restores learning and memory and α-tubulin acetylation in a mouse model for Alzheimer's disease (AD). Our data suggest that this therapeutic effect is, at least in part, linked to the observation that loss of HDAC6 renders neurons resistant to amyloid-β-mediated impairment of mitochondrial trafficking. Thus, our study suggests that targeting HDAC6 could be a suitable strategy to ameliorate cognitive decline observed in AD.
264 citations
Cites background from "HDAC6 inhibitors reverse axonal los..."
...Another recent study found that inhibition of HDAC6 rescues axonal degeneration in a model of Charcot-Marie-Tooth disease (d’Ydewalle et al, 2011)....
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References
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TL;DR: A proteomic-scale analysis of protein acetylation suggests that it is an important biological regulatory mechanism and the regulatory scope of lysine acetylations is broad and comparable with that of other major posttranslational modifications.
Abstract: Lysine acetylation is a reversible posttranslational modification of proteins and plays a key role in regulating gene expression. Technological limitations have so far prevented a global analysis of lysine acetylation's cellular roles. We used high-resolution mass spectrometry to identify 3600 lysine acetylation sites on 1750 proteins and quantified acetylation changes in response to the deacetylase inhibitors suberoylanilide hydroxamic acid and MS-275. Lysine acetylation preferentially targets large macromolecular complexes involved in diverse cellular processes, such as chromatin remodeling, cell cycle, splicing, nuclear transport, and actin nucleation. Acetylation impaired phosphorylation-dependent interactions of 14-3-3 and regulated the yeast cyclin-dependent kinase Cdc28. Our data demonstrate that the regulatory scope of lysine acetylation is broad and comparable with that of other major posttranslational modifications.
3,787 citations
TL;DR: The results show that HDAC6 is the tubulin deacetylase, and provide evidence that reversible acetylation regulates important biological processes beyond histone metabolism and gene transcription, including microtubule-dependent cell motility.
Abstract: Reversible acetylation of α-tubulin has been implicated in regulating microtubule stability and function1. The distribution of acetylated α-tubulin is tightly controlled and stereotypic. Acetylated α-tubulin is most abundant in stable microtubules but is absent from dynamic cellular structures such as neuronal growth cones and the leading edges of fibroblasts1,2. However, the enzymes responsible for regulating tubulin acetylation and deacetylation are not known. Here we report that a member of the histone deacetylase family, HDAC6, functions as a tubulin deacetylase. HDAC6 is localized exclusively in the cytoplasm, where it associates with microtubules and localizes with the microtubule motor complex containing p150glued (ref. 3). In vivo, the overexpression of HDAC6 leads to a global deacetylation of α-tubulin, whereas a decrease in HDAC6 increases α-tubulin acetylation. In vitro, purified HDAC6 potently deacetylates α-tubulin in assembled microtubules. Furthermore, overexpression of HDAC6 promotes chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility. Our results show that HDAC6 is the tubulin deacetylase, and provide evidence that reversible acetylation regulates important biological processes beyond histone metabolism and gene transcription.
2,096 citations
"HDAC6 inhibitors reverse axonal los..." refers background in this paper
...HDAC6, a class II histone deacetylase, is the major enzyme with α-tubulin deacetylating activit...
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TL;DR: It is shown that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot–Marie–Tooth type IIa, is enriched at the ER–mitochondria interface, and that it tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca2+ uptake.
Abstract: Juxtaposition between endoplasmic reticulum (ER) and mitochondria is a common structural feature, providing the physical basis for intercommunication during Ca(2+) signalling; yet, the molecular mechanisms controlling this interaction are unknown. Here we show that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot-Marie-Tooth type IIa, is enriched at the ER-mitochondria interface. Ablation or silencing of mitofusin 2 in mouse embryonic fibroblasts and HeLa cells disrupts ER morphology and loosens ER-mitochondria interactions, thereby reducing the efficiency of mitochondrial Ca(2+) uptake in response to stimuli that generate inositol-1,4,5-trisphosphate. An in vitro assay as well as genetic and biochemical evidences support a model in which mitofusin 2 on the ER bridges the two organelles by engaging in homotypic and heterotypic complexes with mitofusin 1 or 2 on the surface of mitochondria. Thus, mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca(2+) uptake.
2,027 citations
"HDAC6 inhibitors reverse axonal los..." refers background in this paper
...Mutant MFN2 caused an increase in tethering to the endoplasmic reticulum, which impaired axonal transport of mitochondria in transfected DRG neuron...
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TL;DR: Why mitochondria move and how they move is reviewed, focusing particularly on recent studies of transport regulation, which implicate control of motor activity by specific cell-signaling pathways, regulation of motor access to transport tracks and static microtubule–mitochondrion linkers.
Abstract: Organelle transport is vital for the development and maintenance of axons, in which the distances between sites of organelle biogenesis, function, and recycling or degradation can be vast. Movement of mitochondria in axons can serve as a general model for how all organelles move: mitochondria are easy to identify, they move along both microtubule and actin tracks, they pause and change direction, and their transport is modulated in response to physiological signals. However, they can be distinguished from other axonal organelles by the complexity of their movement and their unique functions in aerobic metabolism, calcium homeostasis and cell death. Mitochondria are thus of special interest in relating defects in axonal transport to neuropathies and degenerative diseases of the nervous system. Studies of mitochondrial transport in axons are beginning to illuminate fundamental aspects of the distribution mechanism. They use motors of one or more kinesin families, along with cytoplasmic dynein, to translocate along microtubules, and bidirectional movement may be coordinated through interaction between dynein and kinesin-1. Translocation along actin filaments is probably driven by myosin V, but the protein(s) that mediate docking with actin filaments remain unknown. Signaling through the PI 3-kinase pathway has been implicated in regulation of mitochondrial movement and docking in the axon, and additional mitochondrial linker and regulatory proteins, such as Milton and Miro, have recently been described.
1,231 citations
"HDAC6 inhibitors reverse axonal los..." refers background in this paper
...Reduced acetylation of α-tubulin in mutant HSPB1 nerves Mitochondria are mainly transported along microtubules consisting of polymerized tubuli...
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TL;DR: It is suggested that small molecules that selectively inhibit HDAC6-mediated α-tubulin deacetylation, a first example of which is tubacin, might have therapeutic applications as antimetastatic and antiangiogenic agents.
Abstract: Protein acetylation, especially histone acetylation, is the subject of both research and clinical investigation. At least four small-molecule histone deacetylase inhibitors are currently in clinical trials for the treatment of cancer. These and other inhibitors also affect microtubule acetylation. A multidimensional, chemical genetic screen of 7,392 small molecules was used to discover “tubacin,” which inhibits α-tubulin deacetylation in mammalian cells. Tubacin does not affect the level of histone acetylation, gene-expression patterns, or cell-cycle progression. We provide evidence that class II histone deacetylase 6 (HDAC6) is the intracellular target of tubacin. Only one of the two catalytic domains of HDAC6 possesses tubulin deacetylase activity, and only this domain is bound by tubacin. Tubacin treatment did not affect the stability of microtubules but did decrease cell motility. HDAC6 overexpression disrupted the localization of p58, a protein that mediates binding of Golgi elements to microtubules. Our results highlight the role of α-tubulin acetylation in mediating the localization of microtubule-associated proteins. They also suggest that small molecules that selectively inhibit HDAC6-mediated α-tubulin deacetylation, a first example of which is tubacin, might have therapeutic applications as antimetastatic and antiangiogenic agents.
1,073 citations