title: Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar Purkinje cells.
abstract: Spinocerebellar ataxia type 3 (SCA3) is caused by the abnormal expansion of CAG repeats within the ataxin-3 gene. Previously, we generated transgenic mice (SCA3 mice) that express a truncated form of ataxin-3 containing abnormally expanded CAG repeats specifically in cerebellar Purkinje cells (PCs). Here, we further characterize these SCA3 mice. Whole-cell patch-clamp analysis of PCs from advanced-stage SCA3 mice revealed a significant decrease in membrane capacitance due to poor dendritic arborization and the complete absence of metabotropic glutamate receptor subtype1 (mGluR1)-mediated retrograde suppression of synaptic transmission at parallel fiber terminals, with an overall preservation of AMPA receptor-mediated fast synaptic transmission. Because these cerebellar phenotypes are reminiscent of retinoic acid receptor-related orphan receptor α (RORα)-defective staggerer mice, we examined the levels of RORα in the SCA3 mouse cerebellum by immunohistochemistry and found a marked reduction of RORα in the nuclei of SCA3 mouse PCs. To confirm that the defects in SCA3 mice were caused by postnatal deposition of mutant ataxin-3 in PCs, not by genome disruption via transgene insertion, we tried to reduce the accumulation of mutant ataxin-3 in developing PCs by viral vector-mediated expression of CRAG, a molecule that facilitates the degradation of stress proteins. Concomitant with the removal of mutant ataxin-3, CRAG-expressing PCs had greater numbers of differentiated dendrites compared to non-transduced PCs and exhibited retrograde suppression of synaptic transmission following mGluR1 activation. These results suggest that postnatal nuclear accumulation of mutant ataxin-3 disrupts dendritic differentiation and mGluR-signaling in SCA3 mouse PCs, and this disruption may be caused by a defect in a RORα-driven transcription pathway.
authors: Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan.
authors: Ayumu
authors: A
authors: Konno
authors: Anton N
authors: AN
authors: Shuvaev
authors: Noriko
authors: N
authors: Miyake
authors: Koichi
authors: K
authors: Miyake
authors: Akira
authors: A
authors: Iizuka
authors: Serina
authors: S
authors: Matsuura
authors: Fathul
authors: F
authors: Huda
authors: Kazuhiro
authors: K
authors: Nakamura
authors: Shigeru
authors: S
authors: Yanagi
authors: Takashi
authors: T
authors: Shimada
authors: Hirokazu
authors: H
authors: Hirai
mesh_terms: D000200:Action Potentials; D000818:Animals; D000067699:Ataxin-3; D002467:Cell Nucleus / Q000502:physiology; D002531:Cerebellum / Q000254:growth & development / Q000502:physiology*; D003712:Dendrites / Q000473:pathology / Q000502:physiology*; D025802:Electric Capacitance; D066298:In Vitro Techniques; D017827:Machado-Joseph Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism; D010455:Peptides; D011689:Purkinje Cells / Q000473:pathology / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D009435:Synaptic Transmission; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D010455:Peptides; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D014157:Transcription Factors; C104077:metabotropic glutamate receptor type 1; C097188:polyglutamine; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse
references: Eur J Neurosci. 2009 Aug;30(3):355-65
references: 19614753
references: Nat Biotechnol. 2009 Jan;27(1):59-65
references: 19098898
references: Cerebellum. 2006;5(2):134-45
references: 16818388
references: Mol Ther. 2011 Jun;19(6):1058-69
references: 21487395
references: Acta Neuropathol. 2012 Jul;124(1):1-21
references: 22684686
references: Cell. 2006 Nov 17;127(4):669-71
references: 17110325
references: Brain Res. 2011 May 10;1389:19-26
references: 21397590
references: Annu Rev Neurosci. 2000;23:217-47
references: 10845064
references: Nat Med. 2011 Oct 16;17(11):1445-7
references: 22001907
references: Eur J Hum Genet. 2000 Jan;8(1):4-18
references: 10713882
references: Nat Neurosci. 2005 Jun;8(6):776-81
references: 15864304
references: Neurosci Lett. 2008 Sep 26;443(1):7-11
references: 18675313
references: Neuron. 2010 Feb 11;65(3):291-2
references: 20159441
references: J Nippon Med Sch. 2012;79(6):394-402
references: 23291836
references: Nature. 1996 Feb 22;379(6567):736-9
references: 8602221
references: Nat Neurosci. 2003 Oct;6(10):1048-57
references: 14502290
references: Cell. 2006 Nov 17;127(4):697-708
references: 17110330
references: Brain Res. 2009 Feb 19;1255:9-17
references: 19103174
references: J Neurosci. 2011 Sep 7;31(36):13002-14
references: 21900579
references: Physiol Rev. 2009 Jan;89(1):309-80
references: 19126760
references: EMBO Rep. 2008 Apr;9(4):393-9
references: 18344973
references: J Physiol. 2007 Jan 15;578(Pt 2):545-50
references: 17110417
references: J Cell Biol. 2006 Feb 13;172(4):497-504
references: 16461359
references: J Physiol. 2011 Jul 1;589(Pt 13):3191-209
references: 21558162
references: Science. 1962 Aug 24;137(3530):610-2
references: 13912552
references: Curr Opin Neurobiol. 2007 Jun;17(3):360-5
references: 17419048
references: Neuron. 2001 Aug 16;31(3):463-75
references: 11516402
references: Nat Genet. 1994 Nov;8(3):221-8
references: 7874163
references: Neurobiol Dis. 2009 Sep;35(3):457-65
references: 19573599
references: Hum Gene Ther. 1996 Mar 1;7(4):507-13
references: 8800745