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 Ròna-Vörös, Rana Soylu, Elli Mikrouli, Yves Larmet, Frédérique René, Jose Luis Gonzalez de Aguilar, Jean Philippe Loeffler, Hans Peter Müller, Selina Bucher, Thomas Kaulisch, Heiko G. Niessen, Julia Tillmanns, Kristina Fischer, Birgit Schwalenstöcker, Jan Kassubek, Bernd Pichler, Detlef Stiller, Åsa PetersenAlbert C. Ludolph, Luc Dupuis

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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 p150Glued. 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 (US)
Pages (from-to)4385-4398
Number of pages14
JournalHuman molecular genetics
Issue number22
StatePublished - Nov 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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