Histone Deacetylase 6 Inhibition Compensates for the Transport Deficit in Huntington's Disease by Increasing Tubulin Acetylation

Dompierre, Jim; Godin, Juliette D.; Charrin, Bénédicte C.; Cordelières, Fabrice P.; King, Stephen J.; Humbert, Sandrine; Saudou, Frédéric

doi:10.1523/jneurosci.0037-07.2007

Cited by 685 publications

(700 citation statements)

References 62 publications

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“…A recent study correlated the amelioration of memory function induced by HDAC6 deletion in a model of AD, with the rescue in mitochondrial trafficking 46 . HDAC6 inhibition also improved the impaired mitochondrial transport in a model of CharcotMarie-Tooth disease 47 , and nonspecific HDAC inhibitors, such as suberoylanilide hydroxamic acid and TSA, application alleviates the impaired axonal transport of vesicles by enhancing the interaction between kinesin-1 and MT in a mouse model of Huntington's disease 48 .…”

Section: Discussionmentioning

confidence: 99%

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

et al. 2015

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Maintenance of neuronal polarity and regulation of cytoskeletal dynamics are vital during development and to uphold synaptic activity in neuronal networks. Here we show that soluble b-amyloid (Ab) disrupts actin and microtubule (MT) dynamics via activation of RhoA and inhibition of histone deacetylase 6 (HDAC6) in cultured hippocampal neurons. The contact of Ab with the extracellular membrane promotes RhoA activation, leading to growth cone collapse and neurite retraction, which might be responsible for hampered neuronal pathfinding and migration in Alzheimer's disease (AD). The inhibition of HDAC6 by Ab increases the level of heterodimeric acetylated tubulin and acetylated tau, both of which have been found altered in AD. We also find that the loss of HDAC6 activity perturbs the integrity of axon initial segment (AIS), resulting in mislocalization of ankyrin G and increased MT instability in the AIS concomitant with loss of polarized localization of tau and impairment of action potential firing.

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Section: Discussionmentioning

confidence: 99%

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

et al. 2015

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“…However, the overexpression of PCAF was not sufficient to ameliorate the HD phenotype in transgenic flies, suggesting that therapeutic strategies aimed at increasing PCAF protein levels are likely ineffective in ameliorating HD pathology; notably, increasing the HAT activity of PCAF has not been tested, and other trials targeting PCAF activity are needed [86]. Increasing the acetylation of histones and non-histone proteins via the use of HDAC inhibitors also counteracts neurodegeneration [8,88,[99][100][101]. Intriguingly, McFarlan et al [96] also demonstrated that HDAC inhibition reestablished altered transcriptional levels in the striatum of the R6/2 mouse model, but only slightly improved H3ac binding to specific promoter, emphasizing the idea that the overall chromatin environment surrounding a gene would be more adapted to therapeutic targeting than simply increasing the acetylation of the histones.…”

Section: Hat Impairment In Neurodegenerative Disordersmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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“…Inhibitors of Histone deacetylases (HDACs), which are currently being used as cancer therapeutics 68 , influence axonal transport through increased acetylation of α-tubulin, enhancing its binding to kinesin 4,69 . The modulation of HAP1 binding to mHtt would likely be harder to achieve, since the strengthening of a protein-protein interaction is generally not considered a druggable intervention.…”

Section: Trafficking Defects In Hd and Ad: Targeting Microtubule-assomentioning

confidence: 99%

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

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Neurodegenerative diseases exemplified by Alzheimer's and Huntington disease are characterized by the progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Even though there are differences in the exact sites of pathology and clinical profiles only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of common therapeutic targets for drug development. Huntington disease with a monogenic cause and the possibility to accurately identify pre-manifest mutation carriers could be exploited as a 'model' for Alzheimer's disease to test the efficacy of therapeutic interventions targeting shared pathogenic pathways.

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Histone Deacetylase 6 Inhibition Compensates for the Transport Deficit in Huntington's Disease by Increasing Tubulin Acetylation

Cited by 685 publications

References 62 publications

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

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