Huntingtin Controls Neurotrophic Support and Survival of Neurons by Enhancing BDNF Vesicular Transport along Microtubules

Gauthier, Laurent; Charrin, Bénédicte C.; Borrell-Pagès, María; Dompierre, Jim; Rangone, Hélène; Cordelières, Fabrice P.; Mey, J. De; MacDonald, Marcy E.; Leßmann, Volkmar; Humbert, Sandrine

doi:10.1016/j.cell.2004.06.018

Cited by 1,003 publications

(1,084 citation statements)

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“…Although we cannot compare these 2 sets of findings statistically and so must proceed with caution, the NODDI and DTI analyses combined do suggest that the widespread increased diffusivity in pre‐HD can in principle be explained by reductions in the number of axons within the fibers of white matter pathways. This is highly compatible with the evidence of axonal degeneration in animal studies of pre‐HD 12, 13. It should be noted, however, that although it is biologically plausible that reduced NDI is underscored by changes in axonal density, there may also be an effect of myelin loss.…”

Section: Discussionsupporting

confidence: 83%

In vivo characterization of white matter pathology in premanifest huntington's disease

Zhang

Gregory

Scahill

et al. 2018

Annals of Neurology

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ObjectiveHuntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder, providing an ideal model for understanding brain changes occurring in the years prior to disease onset. Diffusion tensor imaging (DTI) studies show widespread white matter disorganization in the early premanifest stages (pre‐HD). However, although DTI has proved informative, it provides only limited information about underlying changes in tissue properties. Neurite orientation dispersion and density imaging (NODDI) is a novel magnetic resonance imaging (MRI) technique for characterizing axonal pathology more specifically, providing metrics that separately quantify axonal density and axonal organization. Here, we provide the first in vivo characterization of white matter pathology in pre‐HD using NODDI.MethodsDiffusion‐weighted MRI data that support DTI and NODDI were acquired from 38 pre‐HD and 45 control participants. Using whole‐brain and region‐of‐interest analyses, NODDI metrics were compared between groups and correlated with clinical scores of disease progression. Whole‐brain changes in DTI metrics were also examined.ResultsThe pre‐HD group displayed widespread reductions in axonal density compared with control participants; this correlated with measures of clinical disease progression in the body and genu of the corpus callosum. There was also evidence in the pre‐HD group of increased coherence of axonal packing in the white matter surrounding the basal ganglia.InterpretationOur findings suggest that reduced axonal density is one of the major factors underlying white matter pathology in pre‐HD, coupled with altered local organization in areas surrounding the basal ganglia. NODDI metrics show promise in providing more specific information about the biological processes underlying HD and neurodegeneration per se. Ann Neurol 2018;84:497–504

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Section: Discussionsupporting

confidence: 83%

In vivo characterization of white matter pathology in premanifest huntington's disease

Zhang

Gregory

Scahill

et al. 2018

Annals of Neurology

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“…Moreover, the acetylation of tubulin (likely through cytoplasmic acetyltransferases) regulates anterograde and retrograde axonal transport through signaling the anchoring of molecular motors, such as Kinesin-1 to microtubules [93]. As a decrease of acetylated-tubulin has been observed in postmortem brain samples [94], one could predict that a disruption of intracellular trafficking could occur in HD patients, as observed in HD mice neuronal culture and leading to the alteration to the alteration of vesicular BDNF transport [95].…”

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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“…Striatal MSNs rely on BDNF release from innervating cortical neurons for their normal functioning and survival, which makes axonal trafficking of BDNF from the cell body of cortical neurons to the synapse an important process 60 . Defects in intracellular trafficking have been suggested as a cause for the reduced BDNF levels in the brains of patients with HD or AD 60,61 .…”

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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Huntingtin Controls Neurotrophic Support and Survival of Neurons by Enhancing BDNF Vesicular Transport along Microtubules

Cited by 1,003 publications

References 45 publications

In vivo characterization of white matter pathology in premanifest huntington's disease

In vivo characterization of white matter pathology in premanifest huntington's disease

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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