A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons
| العنوان: | A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons |
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| المؤلفون: | Krisztina Rona-Voros, Kerstin E. Braunstein, Selina Bucher, Heiko G. Niessen, Birgit Schwalenstöcker, Judith Eschbach, Yves Larmet, Åsa Petersén, Elli Mikrouli, Luc Dupuis, Hans-Peter Müller, Thomas Kaulisch, Julia Tillmanns, Rana Soylu, Kristina Fischer, Jan Kassubek, Detlef Stiller, Jean Philippe Loeffler, Albert C. Ludolph, Frédérique René, Jose Luis Gonzalez De Aguilar, Bernd J. Pichler |
| المصدر: | Human Molecular Genetics. 19:4385-4398 |
| بيانات النشر: | Oxford University Press (OUP), 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Male, Heterozygote, Dopamine, Dynein, Substantia nigra, macromolecular substances, Striatum, Biology, Mice, Dynein ATPase, Basal ganglia, Neurites, Genetics, medicine, Animals, Point Mutation, Molecular Biology, Cells, Cultured, Genetics (clinical), Neurons, Mice, Inbred C3H, Behavior, Animal, Receptors, Dopamine D2, Dyneins, Articles, Dynactin Complex, General Medicine, Embryo, Mammalian, Corpus Striatum, Substantia Nigra, Huntington Disease, medicine.anatomical_structure, nervous system, Nerve Degeneration, Dynactin, Axoplasmic transport, Neuron, Atrophy, Microtubule-Associated Proteins, Neuroscience |
| الوصف: | The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntington's disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration. To provide such evidence, we used here a mouse strain carrying a point mutation in the dynein heavy chain gene that impairs retrograde axonal transport. These mice exhibited motor and behavioural abnormalities including hindlimb clasping, early muscle weakness, incoordination and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in positron emission tomography SCAN and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. Altogether, these findings provide a direct genetic evidence for the requirement of dynein for the morphology and function of striatal neurons. Our study supports a role for dynein dysfunction in the pathogenesis of neurodegenerative disorders of the basal ganglia, such as Perry syndrome and HD. |
| تدمد: | 1460-2083 0964-6906 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f7fef43044b7287fbdb4402673382b5c https://doi.org/10.1093/hmg/ddq361 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f7fef43044b7287fbdb4402673382b5c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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