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

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A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons. / Braunstein, Kerstin E.; Eschbach, Judith; Rona-Voeroes, Krisztina; Soylu, Rana; Mikrouli, Elli; Larmet, Yves; Rene, Frederique; De Aguilar, Jose-Luis Gonzalez; Loeffler, Jean-Philippe; Mueller, Hans-Peter; Bucher, Selina; Kaulisch, Thomas; Niessen, Heiko G.; Tillmanns, Julia; Fischer, Kristina; Schwalenstoecker, Birgit; Kassubek, Jan; Pichler, Bernd; Stiller, Detlef; Petersén, Åsa; Ludolph, Albert C.; Dupuis, Luc.

In: Human Molecular Genetics, Vol. 19, No. 22, 2010, p. 4385-4398.

Research output: Contribution to journalArticle

Harvard

Braunstein, KE, Eschbach, J, Rona-Voeroes, K, Soylu, R, Mikrouli, E, Larmet, Y, Rene, F, De Aguilar, J-LG, Loeffler, J-P, Mueller, H-P, Bucher, S, Kaulisch, T, Niessen, HG, Tillmanns, J, Fischer, K, Schwalenstoecker, B, Kassubek, J, Pichler, B, Stiller, D, Petersén, Å, Ludolph, AC & Dupuis, L 2010, 'A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons', Human Molecular Genetics, vol. 19, no. 22, pp. 4385-4398. https://doi.org/10.1093/hmg/ddq361

APA

CBE

Braunstein KE, Eschbach J, Rona-Voeroes K, Soylu R, Mikrouli E, Larmet Y, Rene F, De Aguilar J-LG, Loeffler J-P, Mueller H-P, Bucher S, Kaulisch T, Niessen HG, Tillmanns J, Fischer K, Schwalenstoecker B, Kassubek J, Pichler B, Stiller D, Petersén Å, Ludolph AC, Dupuis L. 2010. A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons. Human Molecular Genetics. 19(22):4385-4398. https://doi.org/10.1093/hmg/ddq361

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Braunstein, Kerstin E. ; Eschbach, Judith ; Rona-Voeroes, Krisztina ; Soylu, Rana ; Mikrouli, Elli ; Larmet, Yves ; Rene, Frederique ; De Aguilar, Jose-Luis Gonzalez ; Loeffler, Jean-Philippe ; Mueller, Hans-Peter ; Bucher, Selina ; Kaulisch, Thomas ; Niessen, Heiko G. ; Tillmanns, Julia ; Fischer, Kristina ; Schwalenstoecker, Birgit ; Kassubek, Jan ; Pichler, Bernd ; Stiller, Detlef ; Petersén, Åsa ; Ludolph, Albert C. ; Dupuis, Luc. / A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 22. pp. 4385-4398.

RIS

TY - JOUR

T1 - A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons

AU - Braunstein, Kerstin E.

AU - Eschbach, Judith

AU - Rona-Voeroes, Krisztina

AU - Soylu, Rana

AU - Mikrouli, Elli

AU - Larmet, Yves

AU - Rene, Frederique

AU - De Aguilar, Jose-Luis Gonzalez

AU - Loeffler, Jean-Philippe

AU - Mueller, Hans-Peter

AU - Bucher, Selina

AU - Kaulisch, Thomas

AU - Niessen, Heiko G.

AU - Tillmanns, Julia

AU - Fischer, Kristina

AU - Schwalenstoecker, Birgit

AU - Kassubek, Jan

AU - Pichler, Bernd

AU - Stiller, Detlef

AU - Petersén, Åsa

AU - Ludolph, Albert C.

AU - Dupuis, Luc

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddq361

DO - 10.1093/hmg/ddq361

M3 - Article

VL - 19

SP - 4385

EP - 4398

JO - Human Molecular Genetics

T2 - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 22

ER -