Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3epsilon haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration.
Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1). Both WT and mutant ATXN1 interact with 14-3-3 proteins, and 14-3-3 overexpression stabilizes ATXN1 levels in cells and increases ATXN1 toxicity in flies. To determine whether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca1(154Q/+) mice to mice lacking one allele of 14-3-3ε. 14-3-3ε haploinsufficiency rescued cerebellar pathology and motor phenotypes but, surprisingly, not weight loss, respiratory dysfunction, or premature lethality. Biochemical studies revealed that reducing 14-3-3ε levels exerted different effects in two brain regions especially vulnerable in SCA1: Although diminishing levels of both WT and mutant ATXN1 in the cerebellum, 14-3-3ε haploinsufficiency did not alter ATXN1 levels in the brainstem. Furthermore, 14-3-3ε haploinsufficiency decreased the incorporation of expanded ATXN1 into its large toxic complexes in the cerebellum but not in the brainstem, and the distribution of ATXN1's small and large native complexes differed significantly between the two regions. These data suggest that distinct pathogenic mechanisms operate in different vulnerable brain regions, adding another level of complexity to SCA1 pathogenesis.
Department of Molecular and Human Genetics, and Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
Paymaan
P
Jafar-Nejad
Christopher S
CS
Ward
Ronald
R
Richman
Harry T
HT
Orr
Huda Y
HY
Zoghbi
D048948:14-3-3 Proteins / Q000235:genetics*; D000483:Alleles; D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D001921:Brain / Q000473:pathology; D002460:Cell Line; D057895:Haploinsufficiency; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D020754:Spinocerebellar Ataxias / Q000235:genetics*
D048948:14-3-3 Proteins; C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins
Cell. 1995 Sep 22;82(6):937-48
7553854
Neuron. 2010 Sep 23;67(6):929-35
20869591
Nat Rev Genet. 2005 Oct;6(10):743-55
16205714
Ann N Y Acad Sci. 1999;893:192-202
10672238
J Biol Chem. 2002 Feb 1;277(5):3061-4
11709560
J Mol Biol. 2005 Dec 9;354(4):883-93
16277991
Cell. 2006 Jun 16;125(6):1179-91
16777606
Curr Pharm Des. 2008;14(30):3231-46
19075703
Neuron. 2003 May 8;38(3):375-87
12741986
J Neurol. 2006 Jul;253(7):875-81
16619126
Hum Mol Genet. 2000 Mar 22;9(5):779-85
10749985
Nature. 2008 Apr 10;452(7188):713-8
18337722
Cell. 2003 May 16;113(4):457-68
12757707
Annu Rev Neurosci. 2007;30:575-621
17417937
Hum Mol Genet. 2006 Jun 15;15(12):1984-94
16675531
Trends Biochem Sci. 1992 Dec;17(12):498-501
1471260
J Neurol Neurosurg Psychiatry. 1999 Nov;67(5):695
10577039
Neuron. 2002 Jun 13;34(6):905-19
12086639
Neurochem Res. 2003 Aug;28(8):1265-73
12834267
Acta Neurol Scand. 2010 Nov;122(5):323-8
20002004
FEBS Lett. 1995 Jul 10;368(1):55-8
7615088
Cell. 2002 Oct 18;111(2):209-18
12408865
Nat Genet. 2007 Mar;39(3):373-9
17322884
Neuroscience. 2002;109(1):5-14
11784696
J Neurochem. 1999 Jan;72(1):185-95
9886069
Cell. 2005 Aug 26;122(4):633-44
16122429
Cell. 1996 Mar 22;84(6):889-97
8601312
Genome Biol. 2005;6(3):210
15774033
Cell. 1998 Oct 2;95(1):41-53
9778246
Nat Genet. 2003 Jul;34(3):274-85
12796778
Neuron. 2009 Dec 24;64(6):828-40
20064390
Sci STKE. 2005 Aug 09;2005(296):re10
16091624
Semin Cell Biol. 1995 Feb;6(1):29-35
7620119
Cell. 2006 Dec 29;127(7):1335-47
17190598
Biochem Biophys Res Commun. 2003 Jan 17;300(3):679-85
12507503
Plant Mol Biol. 2002 Dec;50(6):993-1010
12516867
Neurosci Lett. 2007 Mar 6;414(2):130-5
17224237