Publications by authors named "Juliette D Godin"

20 Publications

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The structure of the mouse ADAT2/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination.

Nucleic Acids Res 2021 06;49(11):6529-6548

Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104, U 1258, 1 rue Laurent Fries, B.P. 10142, 67404, Illkirch Cedex, France.

Post-transcriptional modification of tRNA wobble adenosine into inosine is crucial for decoding multiple mRNA codons by a single tRNA. The eukaryotic wobble adenosine-to-inosine modification is catalysed by the ADAT (ADAT2/ADAT3) complex that modifies up to eight tRNAs, requiring a full tRNA for activity. Yet, ADAT catalytic mechanism and its implication in neurodevelopmental disorders remain poorly understood. Here, we have characterized mouse ADAT and provide the molecular basis for tRNAs deamination by ADAT2 as well as ADAT3 inactivation by loss of catalytic and tRNA-binding determinants. We show that tRNA binding and deamination can vary depending on the cognate tRNA but absolutely rely on the eukaryote-specific ADAT3 N-terminal domain. This domain can rotate with respect to the ADAT catalytic domain to present and position the tRNA anticodon-stem-loop correctly in ADAT2 active site. A founder mutation in the ADAT3 N-terminal domain, which causes intellectual disability, does not affect tRNA binding despite the structural changes it induces but most likely hinders optimal presentation of the tRNA anticodon-stem-loop to ADAT2.
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http://dx.doi.org/10.1093/nar/gkab436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216470PMC
June 2021

Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity.

Nat Commun 2020 05 15;11(1):2441. Epub 2020 May 15.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.

KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.
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http://dx.doi.org/10.1038/s41467-020-16294-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229210PMC
May 2020

TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis.

Nat Commun 2019 05 13;10(1):2129. Epub 2019 May 13.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400, Illkirch, France.

De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors' proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1 mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1 animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1 mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations.
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http://dx.doi.org/10.1038/s41467-019-10081-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513894PMC
May 2019

p27 Modulates Axonal Transport by Regulating α-Tubulin Acetyltransferase 1 Stability.

Cell Rep 2018 05;23(8):2429-2442

Liege Université, GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), 4000 Liège, Belgium. Electronic address:

The protein p27 plays roles that extend beyond cell-cycle regulation during cerebral cortex development, such as the regulation of neuronal migration and neurite branching via signaling pathways that converge on the actin and microtubule cytoskeletons. Microtubule-dependent transport is essential for the maturation of neurons and the establishment of neuronal connectivity though synapse formation and maintenance. Here, we show that p27 controls the transport of vesicles and organelles along the axon of mice cortical projection neurons in vitro. Moreover, suppression of the p27 ortholog, dacapo, in Drosophila melanogaster disrupts axonal transport in vivo, leading to the reduction of locomotor activity in third instar larvae and adult flies. At the molecular level, p27 stabilizes the α-tubulin acetyltransferase 1, thereby promoting the acetylation of microtubules, a post-translational modification required for proper axonal transport.
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http://dx.doi.org/10.1016/j.celrep.2018.04.083DOI Listing
May 2018

WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy.

Proc Natl Acad Sci U S A 2017 10 12;114(44):E9308-E9317. Epub 2017 Oct 12.

Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France;

The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (, , , and ), thinner ( and ), or absent corpus callosum (), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.
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http://dx.doi.org/10.1073/pnas.1713625114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676932PMC
October 2017

Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development.

Hum Mol Genet 2018 01;27(2):224-238

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France.

Genetic findings reported by our group and others showed that de novo missense variants in the KIF2A gene underlie malformations of brain development called pachygyria and microcephaly. Though KIF2A is known as member of the Kinesin-13 family involved in the regulation of microtubule end dynamics through its ATP dependent MT-depolymerase activity, how KIF2A variants lead to brain malformations is still largely unknown. Using cellular and in utero electroporation approaches, we show here that KIF2A disease-causing variants disrupts projection neuron positioning and interneuron migration, as well as progenitors proliferation. Interestingly, further dissection of this latter process revealed that ciliogenesis regulation is also altered during progenitors cell cycle. Altogether, our data suggest that deregulation of the coupling between ciliogenesis and cell cycle might contribute to the pathogenesis of KIF2A-related brain malformations. They also raise the issue whether ciliogenesis defects are a hallmark of other brain malformations, such as those related to tubulins and MT-motor proteins variants.
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http://dx.doi.org/10.1093/hmg/ddx384DOI Listing
January 2018

Elongator controls cortical interneuron migration by regulating actomyosin dynamics.

Cell Res 2016 Oct 27;26(10):1131-1148. Epub 2016 Sep 27.

GIGA-Neurosciences, 4000 Liège, Belgium.

The migration of cortical interneurons is a fundamental process for the establishment of cortical connectivity and its impairment underlies several neurological disorders. During development, these neurons are born in the ganglionic eminences and they migrate tangentially to populate the cortical layers. This process relies on various morphological changes that are driven by dynamic cytoskeleton remodelings. By coupling time lapse imaging with molecular analyses, we show that the Elongator complex controls cortical interneuron migration in mouse embryos by regulating nucleokinesis and branching dynamics. At the molecular level, Elongator fine-tunes actomyosin forces by regulating the distribution and turnover of actin microfilaments during cell migration. Thus, we demonstrate that Elongator cell-autonomously promotes cortical interneuron migration by controlling actin cytoskeletal dynamics.
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http://dx.doi.org/10.1038/cr.2016.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113307PMC
October 2016

Dopaminergic neurons differentiating from LRRK2 G2019S induced pluripotent stem cells show early neuritic branching defects.

Sci Rep 2016 09 19;6:33377. Epub 2016 Sep 19.

GIGA-Research, GIGA-Neurosciences, Université de Liège, Belgium.

Some mutations of the LRRK2 gene underlie autosomal dominant form of Parkinson's disease (PD). The G2019S is a common mutation that accounts for about 2% of PD cases. To understand the pathophysiology of this mutation and its possible developmental implications, we developed an in vitro assay to model PD with human induced pluripotent stem cells (hiPSCs) reprogrammed from skin fibroblasts of PD patients suffering from the LRKK2 G2019S mutation. We differentiated the hiPSCs into neural stem cells (NSCs) and further into dopaminergic neurons. Here we show that NSCs bearing the mutation tend to differentiate less efficiently into dopaminergic neurons and that the latter exhibit significant branching defects as compared to their controls.
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http://dx.doi.org/10.1038/srep33377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027571PMC
September 2016

[Unveiling the role of endoplasmic reticulum stress and unfolded protein response in cortical neurogenesis].

Med Sci (Paris) 2016 Jun-Jul;32(6-7):568-71. Epub 2016 Jul 12.

GIGA-Neurosciences, université de Liège, CHU Sart Tilman, Avenue de l'Hopital, 1, Liège 4020, Belgique - Interdisciplinary cluster for applied genoproteomics (GIGA-R), université de Liège, CHU Sart Tilman, Liège 4000, Belgique.

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http://dx.doi.org/10.1051/medsci/20163206014DOI Listing
July 2017

Emerging Roles for the Unfolded Protein Response in the Developing Nervous System.

Trends Neurosci 2016 06 26;39(6):394-404. Epub 2016 Apr 26.

GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Walloon Excellence in Lifesciences and Biotechnology (WELBIO), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium. Electronic address:

The unfolded protein response (UPR) is a homeostatic signaling pathway triggered by protein misfolding in the endoplasmic reticulum (ER). Beyond its protective role, it plays important functions during normal development in response to elevated demand for protein folding. Several UPR effectors show dynamic temporal and spatial expression patterns that correlate with milestones of the central nervous system (CNS) development. Here, we discuss recent studies suggesting that a dynamic regulation of UPR supports generation, maturation, and maintenance of differentiated neurons in the CNS. We further highlight studies supporting a developmental vulnerability of CNS to UPR dysregulation, which underlies neurodevelopmental disorders. We believe that a better understanding of UPR functions may provide novel opportunities for therapeutic strategies to fight ER/UPR-associated human neurological disorders.
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http://dx.doi.org/10.1016/j.tins.2016.04.002DOI Listing
June 2016

Real-time Recordings of Migrating Cortical Neurons from GFP and Cre Recombinase Expressing Mice.

Curr Protoc Neurosci 2016 Jan 4;74:3.29.1-3.29.23. Epub 2016 Jan 4.

GIGA-Neurosciences, University of Liège, Liège, Belgium.

The cerebral cortex is one of the most intricate regions of the brain that requires elaborate cell migration patterns for its development. Experimental observations show that projection neurons migrate radially within the cortical wall, whereas interneurons migrate along multiple tangential paths to reach the developing cortex. Tight regulation of the cell migration processes ensures proper positioning and functional integration of neurons to specific cerebral cortical circuits. Disruption of neuronal migration often leads to cortical dysfunction and/or malformation associated with neurological disorders. Unveiling the molecular control of neuron migration is thus fundamental to understanding the physiological or pathological development of the cerebral cortex. In this unit, protocols allowing detailed analysis of patterns of migration of both interneurons and projection neurons under different experimental conditions (i.e., loss or gain of function) are presented.
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http://dx.doi.org/10.1002/0471142301.ns0329s74DOI Listing
January 2016

A Dynamic Unfolded Protein Response Contributes to the Control of Cortical Neurogenesis.

Dev Cell 2015 Dec;35(5):553-567

GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Walloon Excellence in Lifesciences and Biotechnology (WELBIO), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium. Electronic address:

The cerebral cortex contains layers of neurons sequentially generated by distinct lineage-related progenitors. At the onset of corticogenesis, the first-born progenitors are apical progenitors (APs), whose asymmetric division gives birth directly to neurons. Later, they switch to indirect neurogenesis by generating intermediate progenitors (IPs), which give rise to projection neurons of all cortical layers. While a direct lineage relationship between APs and IPs has been established, the molecular mechanism that controls their transition remains elusive. Here we show that interfering with codon translation speed triggers ER stress and the unfolded protein response (UPR), further impairing the generation of IPs and leading to microcephaly. Moreover, we demonstrate that a progressive downregulation of UPR in cortical progenitors acts as a physiological signal to amplify IPs and promotes indirect neurogenesis. Thus, our findings reveal a contribution of UPR to cell fate acquisition during mammalian brain development.
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http://dx.doi.org/10.1016/j.devcel.2015.11.005DOI Listing
December 2015

MicroRNA targeting of CoREST controls polarization of migrating cortical neurons.

Cell Rep 2014 May 1;7(4):1168-83. Epub 2014 May 1.

GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Walloon Excellence in Lifesciences and Biotechnology (WELBIO), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium. Electronic address:

The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. The molecular basis of these changes remains elusive, and the present work describes how microRNAs (miRNAs) control neuronal polarization during radial migration. We show that miR-22 and miR-124 are expressed in the cortical wall where they target components of the CoREST/REST transcriptional repressor complex, thereby regulating doublecortin transcription in migrating neurons. This molecular pathway underlies radial migration by promoting dynamic multipolar-bipolar cell conversion at early phases of migration, and later stabilization of cell polarity to support locomotion on radial glia fibers. Thus, our work emphasizes key roles of some miRNAs that control radial migration during cerebral corticogenesis.
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http://dx.doi.org/10.1016/j.celrep.2014.03.075DOI Listing
May 2014

Novel functions of core cell cycle regulators in neuronal migration.

Adv Exp Med Biol 2014 ;800:59-74

GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège, 4000, Belgium.

The cerebral cortex is one of the most intricate regions of the brain, which required elaborated cell migration patterns for its development. Experimental observations show that projection neurons migrate radially within the cortical wall, whereas interneurons migrate along multiple tangential paths to reach the developing cortex. Tight regulation of the cell migration processes ensures proper positioning and functional integration of neurons to specific cerebral cortical circuits. Disruption of neuronal migration often lead to cortical dysfunction and/or malformation associated with neurological disorders. Unveiling the molecular control of neuronal migration is thus fundamental to understand the physiological or pathological development of the cerebral cortex. Generation of functional cortical neurons is a complex and stratified process that relies on decision of neural progenitors to leave the cell cycle and generate neurons that migrate and differentiate to reach their final position in the cortical wall. Although accumulating work shed some light on the molecular control of neuronal migration, we currently do not have a comprehensive understanding of how cell cycle exit and migration/differentiation are coordinated at the molecular level. The current chapter tends to lift the veil on this issue by discussing how core cell cycle regulators, and in particular p27(Kip1) acts as a multifunctional protein to control critical steps of neuronal migration through activities that go far beyond cell cycle regulation.
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http://dx.doi.org/10.1007/978-94-007-7687-6_4DOI Listing
April 2014

Huntingtin mediates anxiety/depression-related behaviors and hippocampal neurogenesis.

J Neurosci 2013 May;33(20):8608-20

Institut Curie, CNRS UMR 3306, INSERM U1005, Orsay 91405, France.

Huntington disease (HD) is associated with early psychiatric symptoms including anxiety and depression. Here, we demonstrate that wild-type huntingtin, the protein mutated in HD, modulates anxiety/depression-related behaviors according to its phosphorylation at serines 1181 and 1201. Genetic phospho-ablation at serines 1181 and 1201 in mouse reduces basal levels of anxiety/depression-like behaviors. We observe that the reduction in anxiety/depression-like phenotypes is associated with increased adult hippocampal neurogenesis. By improving the attachment of molecular motors to microtubules, huntingtin dephosphorylation increases axonal transport of BDNF, a crucial factor for hippocampal adult neurogenesis. Consequently, the huntingtin-mediated increased BDNF dynamics lead to an increased delivery and signaling of hippocampal BDNF. These results support the notion that huntingtin participates in anxiety and depression-like behavior and is thus relevant to the etiology of mood disorders and anxiety/depression in HD.
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http://dx.doi.org/10.1523/JNEUROSCI.5110-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618836PMC
May 2013

p27(Kip1) is a microtubule-associated protein that promotes microtubule polymerization during neuron migration.

Dev Cell 2012 Oct 27;23(4):729-44. Epub 2012 Sep 27.

GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium.

The migration of cortical interneurons is characterized by extensive morphological changes that result from successive cycles of nucleokinesis and neurite branching. Their molecular bases remain elusive, and the present work describes how p27(Kip1) controls cell-cycle-unrelated signaling pathways to regulate these morphological remodelings. Live imaging reveals that interneurons lacking p27(Kip1) show delayed tangential migration resulting from defects in both nucleokinesis and dynamic branching of the leading process. At the molecular level, p27(Kip1) is a microtubule-associated protein that promotes polymerization of microtubules in extending neurites, thereby contributing to tangential migration. Furthermore, we show that p27(Kip1) controls actomyosin contractions that drive both forward translocation of the nucleus and growth cone splitting. Thus, p27(Kip1) cell-autonomously controls nucleokinesis and neurite branching by regulating both actin and microtubule cytoskeletons.
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http://dx.doi.org/10.1016/j.devcel.2012.08.006DOI Listing
October 2012

Mitotic spindle: focus on the function of huntingtin.

Int J Biochem Cell Biol 2011 Jun 23;43(6):852-6. Epub 2011 Mar 23.

Institut Curie, Orsay, France.

Mitotic spindle assembly and orientation are tightly regulated to allow the appropriate segregation of genetic material and cell fate determinants during symmetric and asymmetric divisions. Microtubules and many proteins including the dynein/dynactin complex and the large nuclear mitotic apparatus NuMA protein, are fundamental players in these mechanisms. A recent study reported that huntingtin regulates spindle orientation by ensuring the proper localization of the p150(Glued) subunit of dynactin, dynein and NuMA. This function of huntingtin is conserved in Drosophila. Among other events, spindle orientation influences the fate of daughter cells. In agreement with this, huntingtin changes the direction of division of mouse cortical progenitors and promotes neurogenesis in the neocortex. We will also discuss the involvement of mitotic spindle components in neuronal disorders.
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http://dx.doi.org/10.1016/j.biocel.2011.03.009DOI Listing
June 2011

Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis.

Neuron 2010 Aug;67(3):392-406

Institut Curie, Orsay F-91405, France.

Huntingtin is the protein mutated in Huntington's disease, a devastating neurodegenerative disorder. We demonstrate here that huntingtin is essential to control mitosis. Huntingtin is localized at spindle poles during mitosis. RNAi-mediated silencing of huntingtin in cells disrupts spindle orientation by mislocalizing the p150(Glued) subunit of dynactin, dynein, and the large nuclear mitotic apparatus NuMA protein. This leads to increased apoptosis following mitosis of adherent cells in vitro. In vivo inactivation of huntingtin by RNAi or by ablation of the Hdh gene affects spindle orientation and cell fate of cortical progenitors of the ventricular zone in mouse embryos. This function is conserved in Drosophila, the specific disruption of Drosophila huntingtin in neuroblast precursors leading to spindle misorientation. Moreover, Drosophila huntingtin restores spindle misorientation in mammalian cells. These findings reveal an unexpected role for huntingtin in dividing cells, with potential important implications in health and disease.
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http://dx.doi.org/10.1016/j.neuron.2010.06.027DOI Listing
August 2010

Mutant huntingtin-impaired degradation of beta-catenin causes neurotoxicity in Huntington's disease.

EMBO J 2010 Jul 8;29(14):2433-45. Epub 2010 Jun 8.

Institut Curie, Orsay, France.

Huntington's disease (HD) is a fatal neurodegenerative disorder causing selective neuronal death in the brain. Dysfunction of the ubiquitin-proteasome system may contribute to the disease; however, the exact mechanisms are still unknown. We report here a new pathological mechanism by which mutant huntingtin specifically interferes with the degradation of beta-catenin. Huntingtin associates with the beta-catenin destruction complex that ensures its equilibrated degradation. The binding of beta-catenin to the destruction complex is altered in HD, leading to the toxic stabilization of beta-catenin. As a consequence, the beta-transducin repeat-containing protein (beta-TrCP) rescues polyglutamine (polyQ)-huntingtin-induced toxicity in striatal neurons and in a Drosophila model of HD, through the specific degradation of beta-catenin. Finally, the non-steroidal anti-inflammatory drug indomethacin that decreases beta-catenin levels has a neuroprotective effect in a neuronal model of HD and in Drosophila and increases the lifespan of HD flies. We thus suggest that restoring beta-catenin homeostasis in HD is of therapeutic interest.
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http://dx.doi.org/10.1038/emboj.2010.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910267PMC
July 2010

Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation.

J Neurosci 2007 Mar;27(13):3571-83

Institut Curie and Centre National de la Recherche Scientifique Unité Mixte de Recherche 146, Orsay, France.

A defect in microtubule (MT)-based transport contributes to the neuronal toxicity observed in Huntington's disease (HD). Histone deacetylase (HDAC) inhibitors show neuroprotective effects in this devastating neurodegenerative disorder. We report here that HDAC inhibitors, including trichostatin A (TSA), increase vesicular transport of brain-derived neurotrophic factor (BDNF) by inhibiting HDAC6, thereby increasing acetylation at lysine 40 of alpha-tubulin. MT acetylation in vitro and in cells causes the recruitment of the molecular motors dynein and kinesin-1 to MTs. In neurons, acetylation at lysine 40 of alpha-tubulin increases the flux of vesicles and the subsequent release of BDNF. We show that tubulin acetylation is reduced in HD brains and that TSA compensates for the transport- and release-defect phenotypes that are observed in disease. Our findings reveal that HDAC6 inhibition and acetylation at lysine 40 of alpha-tubulin may be therapeutic targets of interest in disorders such as HD in which intracellular transport is altered.
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http://dx.doi.org/10.1523/JNEUROSCI.0037-07.2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672116PMC
March 2007
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