A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons

Kerstin E. Braunstein, Judith Eschbach, Krisztina Rona-Voeroes, Rana Soylu, Elli Mikrouli, Yves Larmet, Frederique Rene, Jose-Luis Gonzalez De Aguilar, Jean-Philippe Loeffler, Hans-Peter Mueller, Selina Bucher, Thomas Kaulisch, Heiko G. Niessen, Julia Tillmanns, Kristina Fischer, Birgit Schwalenstoecker, Jan Kassubek, Bernd Pichler, Detlef Stiller, Åsa PetersénAlbert C. Ludolph, Luc Dupuis

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)4385-4398
JournalHuman Molecular Genetics
Issue number22
Publication statusPublished - 2010

Subject classification (UKÄ)

  • Medical Genetics


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