Braunstein KE, Eschbach J, Ròna-Vörös K, Soylu R, Mikrouli E, Larmet Y, Rene F, Gonzalez de Aguilar JL, Loeffler JP, Müller HP, Bucher S, Kaulisch T, Niessen HG, Tillmanns J, Fischer K, Schwalenstocker B, Kassubek J, Pichler B, Stiller D, Petersen A, Ludolph AC and Dupuis L.
Department of Neurology, University of Ulm, Ulm, Germany.
Human Molecular Genetics 19: 4385-4398 (2010)
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 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 MRI showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in PET 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 Huntington's disease.