A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons
(2010) In Human Molecular Genetics 19(22). p.4385-4398- 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... (More)
- 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. (Less)
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https://lup.lub.lu.se/record/1753273
- author
- organization
- publishing date
- 2010
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Human Molecular Genetics
- volume
- 19
- issue
- 22
- pages
- 4385 - 4398
- publisher
- Oxford University Press
- external identifiers
-
- wos:000283673500009
- scopus:77958479351
- pmid:20807776
- ISSN
- 0964-6906
- DOI
- 10.1093/hmg/ddq361
- language
- English
- LU publication?
- yes
- id
- d973c471-379b-4733-8292-1e3e9c82d4c8 (old id 1753273)
- date added to LUP
- 2016-04-01 10:44:54
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- 2022-01-26 02:04:08
@article{d973c471-379b-4733-8292-1e3e9c82d4c8,
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.}},
author = {{Braunstein, Kerstin E. and Eschbach, Judith and Rona-Voeroes, Krisztina and Soylu, Rana and Mikrouli, Elli and Larmet, Yves and Rene, Frederique and De Aguilar, Jose-Luis Gonzalez and Loeffler, Jean-Philippe and Mueller, Hans-Peter and Bucher, Selina and Kaulisch, Thomas and Niessen, Heiko G. and Tillmanns, Julia and Fischer, Kristina and Schwalenstoecker, Birgit and Kassubek, Jan and Pichler, Bernd and Stiller, Detlef and Petersén, Åsa and Ludolph, Albert C. and Dupuis, Luc}},
issn = {{0964-6906}},
language = {{eng}},
number = {{22}},
pages = {{4385--4398}},
publisher = {{Oxford University Press}},
series = {{Human Molecular Genetics}},
title = {{A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons}},
url = {{http://dx.doi.org/10.1093/hmg/ddq361}},
doi = {{10.1093/hmg/ddq361}},
volume = {{19}},
year = {{2010}},
}