A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons.
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.
Braunstein
Kerstin E
KE
Department of Neurology, University of Ulm, Ulm, Germany.
Eschbach
Judith
J
Ròna-Vörös
Krisztina
K
Soylu
Rana
R
Mikrouli
Elli
E
Larmet
Yves
Y
René
Frédérique
F
Gonzalez De Aguilar
Jose-Luis
JL
Loeffler
Jean-Philippe
JP
Müller
Hans-Peter
HP
Bucher
Selina
S
Kaulisch
Thomas
T
Niessen
Heiko G
HG
Tillmanns
Julia
J
Fischer
Kristina
K
Schwalenstöcker
Birgit
B
Kassubek
Jan
J
Pichler
Bernd
B
Stiller
Detlef
D
Petersen
Asa
A
Ludolph
Albert C
AC
Dupuis
Luc
L
D000818:Animals; D001284:Atrophy; D001522:Behavior, Animal / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D004298:Dopamine / Q000235:genetics / Q000378:metabolism; D000072159:Dynactin Complex; D004398:Dyneins / Q000235:genetics*; D004622:Embryo, Mammalian; D006579:Heterozygote; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017354:Point Mutation; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
C000606364:Dctn1 protein, mouse; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D017448:Receptors, Dopamine D2; D004398:Dyneins; D004298:Dopamine
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4182-7
17360497
J Neurosci. 2000 Apr 1;20(7):2439-50
10729324
Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1094-108
16730956
J Biol Chem. 2007 Mar 9;282(10):7352-9
17209049
Behav Brain Res. 2001 Nov 29;126(1-2):185-95
11704263
J Neurosci. 2007 Dec 19;27(51):13982-90
18094236
Mol Endocrinol. 2009 May;23(5):620-9
19228793
Mov Disord. 2002 Jul;17(4):748-57
12210870
PLoS One. 2009;4(4):e5292
19390590
Hum Mol Genet. 2008 Sep 15;17(18):2849-62
18579581
Neuron. 2007 Jul 5;55(1):53-68
17610817
Adv Drug Deliv Rev. 2003 Nov 14;55(11):1385-403
14597137
J Neurosci. 2009 Nov 25;29(47):14752-63
19940170
Hum Mol Genet. 2008 Sep 1;17(17):2595-609
18502785
J Neurosci. 2010 Feb 3;30(5):1739-49
20130183
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2647-52
19196984
Orphanet J Rare Dis. 2008 Mar 18;3:7
18348718
Anat Rec. 1991 Dec;231(4):482-97
1793176
J Cell Biol. 2005 May 23;169(4):561-7
15911875
Nat Genet. 2005 Jul;37(7):771-6
15980862
J Neurosci. 2009 Aug 5;29(31):9903-17
19657041
Nat Cell Biol. 2000 Jan;2(1):20-4
10620802
Science. 2003 May 2;300(5620):808-12
12730604
Neurology. 2004 Aug 24;63(4):724-6
15326253
J Neurosci. 2008 Feb 27;28(9):1997-2005
18305234
Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12599-604
18719118
J Nucl Med. 2005 Jun;46(6):964-72
15937307
J Neurosci. 2007 Dec 26;27(52):14515-24
18160659
J Neurochem. 2008 Jul;106(1):83-95
18346199
Nat Neurosci. 2009 Jul;12(7):864-71
19525941
Nat Cell Biol. 2008 Oct;10(10):1172-80
18758451
J Neurosci. 1998 Feb 15;18(4):1261-9
9454836
Cell. 2004 Jul 9;118(1):127-38
15242649
Nature. 1995 Nov 23;378(6555):398-402
7477378
Cell Metab. 2006 Nov;4(5):349-62
17055784
J Neurol Sci. 2010 Feb 15;289(1-2):149-54
19732908
Nat Cell Biol. 2008 Oct;10(10):1164-71
18758452
Brain Res. 2004 Apr 16;1005(1-2):29-35
15044061
Ann Neurol. 2005 May;57(5):687-94
15852399
Cell. 2004 Oct 1;119(1):121-35
15454086
Cell Cycle. 2008 Jul 15;7(14):2241-8
18635969
J Cell Biol. 1993 Dec;123(6 Pt 1):1373-87
8253838
J Biol Chem. 2009 Dec 4;284(49):34103-15
19815545
Nat Genet. 1998 Oct;20(2):198-202
9771716
J Neurosci. 2009 Oct 14;29(41):12776-86
19828789
Exp Neurol. 2009 Jan;215(1):146-52
18952079
J Cell Biol. 2006 Feb 27;172(5):733-45
16505168
EMBO J. 2006 Sep 20;25(18):4372-80
16957779
J Cereb Blood Flow Metab. 2000 Mar;20(3):423-51
10724107
Exp Neurol. 2006 Mar;198(1):271-4
16427626
Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10045-50
17548833
Nat Cell Biol. 2000 Nov;2(11):776-83
11056531
Nat Genet. 2003 Apr;33(4):455-6
12627231
Nat Rev Neurosci. 2010 May;11(5):316-28
20404840
Neuroimage. 2009 Jan 1;44(1):43-50
18691659
J Neurosci. 2008 Oct 22;28(43):10814-24
18945889
J Neurosci. 2004 Apr 28;24(17):4250-8
15115821
Neuroimage. 1996 Dec;4(3 Pt 1):153-8
9345505
Neuron. 2002 May 30;34(5):715-27
12062019
Hum Mol Genet. 2008 Jul 1;17(13):1946-55
18364389
J Neurosci. 2002 Sep 15;22(18):8266-76
12223581
Nat Genet. 2009 Feb;41(2):163-5
19136952
Int J Dev Neurosci. 2006 Apr-May;24(2-3):103-11
16406469
Traffic. 2007 Feb;8(2):124-9
17181772