title: A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons.
abstract: 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.
authors.affiliation: Department of Neurology, University of Ulm, Ulm, Germany.
authors.forename: Kerstin E
authors.initials: KE
authors.lastname: Braunstein
authors.forename: Judith
authors.initials: J
authors.lastname: Eschbach
authors.forename: Krisztina
authors.initials: K
authors.lastname: Ròna-Vörös
authors.forename: Rana
authors.initials: R
authors.lastname: Soylu
authors.forename: Elli
authors.initials: E
authors.lastname: Mikrouli
authors.forename: Yves
authors.initials: Y
authors.lastname: Larmet
authors.forename: Frédérique
authors.initials: F
authors.lastname: René
authors.forename: Jose-Luis
authors.initials: JL
authors.lastname: Gonzalez De Aguilar
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Loeffler
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Müller
authors.forename: Selina
authors.initials: S
authors.lastname: Bucher
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaulisch
authors.forename: Heiko G
authors.initials: HG
authors.lastname: Niessen
authors.forename: Julia
authors.initials: J
authors.lastname: Tillmanns
authors.forename: Kristina
authors.initials: K
authors.lastname: Fischer
authors.forename: Birgit
authors.initials: B
authors.lastname: Schwalenstöcker
authors.forename: Jan
authors.initials: J
authors.lastname: Kassubek
authors.forename: Bernd
authors.initials: B
authors.lastname: Pichler
authors.forename: Detlef
authors.initials: D
authors.lastname: Stiller
authors.forename: Asa
authors.initials: A
authors.lastname: Petersen
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
mesh_terms: D000818:Animals; D001284:Atrophy; D001522:Behavior, Animal / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D004298:Dopamine / Q000235:genetics / Q000378:metabolism; D000072159:Dynactin Complex; D004398:Dyneins / Q000235:genetics*; D004622:Embryo, Mammalian; D006579:Heterozygote; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017354:Point Mutation; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: C000606364:Dctn1 protein, mouse; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D017448:Receptors, Dopamine D2; D004398:Dyneins; D004298:Dopamine
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