ライフサイエンスコーパス: ataxin-7

1 ger association with the wild-type allele of ataxin-7.

2 ork have altered expression in the retina of Ataxin-7(266Q/+) mice suggesting an in vivo functional r

3 ssion of the caspase-7 truncation product of ataxin-7-69Q or -92Q, which removes the putative nuclear

4 y a polyglutamine [poly(Q)] expansion within ataxin-7, a protein of previously unknown function.

5 to determine whether and how polyQ-expanded ataxin-7 affects SAGA catalytic activity.

6 ted or reversed SCA7 motor symptoms, reduced ataxin-7 aggregation in Purkinje cells (PCs), and preven

7 e hippocampus emerged as a principal site of ataxin-7 aggregation without cell loss.

8 lar ataxia type 7 gene and focus on systemic ataxin-7 aggregation.

9 Within this modular complex, Ataxin-7 anchors the deubiquitinase activity to the larg

10 be used to silence the endogenous allele of ataxin 7 and replace it with an exogenous copy of the ge

11 mine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequen

12 and in SCA7 patient material with both anti-ataxin-7 and anti-polyglutamine specific antibodies.

13 We found that ataxin-7 and CRX colocalize and coimmunoprecipitate.

14 e we identified and characterized Drosophila Ataxin-7 and found that reduction of Ataxin-7 protein re

15 RNA interference studies also implicate ataxin-7 and GCN5 in CRX-dependent gene activation, and

16 A polyglutamine-expanded version of ataxin-7 assembles a SAGA complex that is depleted of cr

17 diffuse distribution throughout the nucleus, ataxin-7 associated with the nuclear matrix and the nucl

18 cleavable D266N/D344N form of polyQ-expanded ataxin-7 attenuated cell death, aggregate formation, and

19 results from polyglutamine expansion of the ataxin-7 (ATXN7) protein.

20 subunit of the P/Q-type calcium channel, and ataxin-7 (ATXN7), a component of a chromatin-remodeling

21 Proteolytic processing of ataxin-7 by caspase-7 generates N-terminal toxic polyQ-c

22 thus, suggest that proteolytic processing of ataxin-7 by caspase-7 may contribute to SCA7 disease pat

23 Cleavage of ataxin-7 by the protease caspase-7 has been demonstrated

24 We observed that polyglutamine-expanded ataxin-7 can dramatically suppress CRX transactivation.

25 tion mouse model by inserting a loxP-flanked ataxin-7 cDNA with 92 repeats into the translational sta

26 -7) disrupts the function of visual arrestin-ataxin-7 chimera, it enhances the function of beta-arres

27 a, it enhances the function of beta-arrestin-ataxin-7 chimera.

28 We also detected N-terminal polyQ-expanded ataxin-7 cleavage products in SCA7 transgenic mice simil

29 caspase-7 into the nucleus by polyQ-expanded ataxin-7 correlated with its activation.

30 polyQ-expanded form of ataxin-7 produces an ataxin-7 D266N/D344N protein that is resistant to caspas

31 omised expression of a CRX target gene in an ataxin-7-deficient background.

32 Here, we determined that polyQ-expanded ataxin-7 directly bound the Gcn5 catalytic core of SAGA

33 Although ataxin-7 displays toxicity, forms nuclear aggregates, an

34 nt in the putative phosphate-binding site of ataxin-7) disrupts the function of visual arrestin-ataxi

35 cipitation, it was demonstrated that Crx and ataxin-7 engage in a functionally significant interactio

36 Despite this phenotype rescue, reduced ataxin-7 expression did not result in full recovery of c

37 To inactivate polyQ-ataxin-7 expression in specific cerebellar cell types, w

38 a, which resulted in ~50% reduction of polyQ-ataxin-7 expression.

39 on sequence (NLS) was confirmed by fusing an ataxin-7 fragment with the normally cytoplasmic protein

40 Excision of ataxin-7 from BG partially rescued the behavioral phenot

41 molecular layer thinning, while excision of ataxin-7 from PCs and inferior olive provided significan

42 To gain insight into ataxin-7 function and to decipher the molecular mechanis

43 No clues to ataxin-7 function have been obtained from sequence datab

44 Given this, we studied how ataxin-7 gene expression is regulated.

45 To understand how CTCF regulates ataxin-7 gene expression, we introduced ataxin-7 mini-ge

46 olyglutamine (polyQ) repeat expansion in the ataxin-7 gene.

47 olyglutamine (polyQ) repeat expansion in the ataxin-7 gene.

48 y CAG/polyglutamine repeat expansions in the ataxin-7 gene.

49 axia caused by a CAG repeat expansion in the ataxin-7 gene.

50 antly, in relation to SCA7, poly(Q)-expanded ataxin-7 gets incorporated into STAGA and, in a dominant

51 Here we report that ataxin-7 has a motif of ca. 50 amino acids, related to t

52 neuronal vulnerability, and show that mutant ataxin-7 impairs posttetanic potentiation (PTP).

53 y reported that directed expression of polyQ-ataxin-7 in Bergmann glia (BG) in transgenic mice leads

54 egeneration, and generated mice that express ataxin-7 in Bergmann glia of the cerebellum with the Gfa

55 When we prevented expression of mutant ataxin-7 in BG, PCs, and inferior olive by deriving Gfa2

56 The appearance of truncated ataxin-7 in nuclear aggregates correlates with the onset

57 ence of expression of polyglutamine-expanded ataxin-7 in Purkinje cells, we documented severe Purkinj

58 we examined the subcellular localization of ataxin-7 in transfected COS-1 cells using SCA7 cDNA clon

59 etected an N-terminal truncation fragment of ataxin-7 in transgenic mice and in SCA7 patient material

60 quitinase module is active in the absence of Ataxin-7 in vitro.

61 When we examined the consequences of reduced Ataxin-7 in vivo, we found that flies exhibited pronounc

62 taxin-7 was barely detectable, as was mutant ataxin-7 in young animals; with increasing age, however,

63 In contrast to yeast, where loss of Ataxin-7 inactivates the deubiquitinase and results in i

64 ant-negative phenotype of the polyQ-expanded ataxin-7-incorporated, catalytically inactive SAGA.

65 a two-hybrid assay was performed to identify ataxin-7 interacting proteins.

66 Thus Crx's ataxin-7 interaction domain was localized to its glutami

67 To determine the basis of the Crx-ataxin-7 interaction, Crx and ataxin-7 truncation and po

68 Herein, we show that ataxin-7 interacts with the ATPase subunit S4 of the pro

69 Ataxin-7 is a component of two different transcription c

70 on of both SAGA and SLIK, and that the human ataxin-7 is able to compliment the loss of Sca7 in yeast

71 Here, we report that ataxin-7 is an integral component of the mammalian STAGA

72 Here we report that ataxin-7 is cleaved by caspase-7, and we map two putativ

73 cumulation of the fragment, while unmodified ataxin-7 is degraded.

74 The SCA7 gene product, ataxin-7, is an 897 amino acid protein with an expandabl

75 nerable had relatively high levels of mutant ataxin-7; it is interesting, however, that marked dysfun

76 Modification of ataxin-7 K257 by acetylation promotes accumulation of th

77 We demonstrate that endogenous ataxin-7 localizes to discrete nuclear foci that also co

78 at inhibition of caspase-7 cleavage of polyQ-ataxin-7 may be a promising therapeutic strategy for thi

79 Thus, expanded ataxin-7 may carry out its pathogenic effects in the nuc

80 ates ataxin-7 gene expression, we introduced ataxin-7 mini-genes into mice, and found that CTCF is re

81 modifications of the N-terminal fragment of ataxin-7 modulate turnover and toxicity.

82 It was also established that ataxin-7 must localize to the nucleus to repress Crx tra

83 -7 cleavage site is an important mediator of ataxin-7 neurotoxicity, suggesting that inhibition of ca

84 neuropathology revealed by this reporter and ataxin-7 nuclear inclusions in the vulnerable neurons.

85 f mouse models expressing full-length mutant ataxin-7 or the androgen receptor.

86 uence similarity, we introduced the putative ataxin-7 phosphate-binding site into visual arrestin and

87 cleavage sites in the polyQ-expanded form of ataxin-7 produces an ataxin-7 D266N/D344N protein that i

88 sophila Ataxin-7 and found that reduction of Ataxin-7 protein results in loss of components from the

89 xpansion within the N-terminal region of the ataxin-7 protein, a known subunit of the SAGA complex.

90 Polyglutamine (polyQ) expansion within the ataxin-7 protein, a member of the STAGA [SPT3-TAF(II)31-

91 by a polyglutamine (polyQ) expansion in the ataxin-7 protein, categorizing SCA7 as one member of a l

92 Asp residues at positions 266 and 344 of the ataxin-7 protein.

93 by expansion of a polyglutamine tract in the ataxin-7 protein.

94 xpansion of a polyglutamine tract within the ataxin-7 protein.

95 whether a causal relationship exists between ataxin-7 proteolysis and in vivo SCA7 disease progressio

96 e that glutamine expansion stabilizes mutant ataxin-7, provide an explanation for selective neuronal

97 d adjacent to the caspase-7 cleavage site of ataxin-7 regulates turnover of the truncation product in

98 The ataxin-7 repeat and translation start site are flanked b

99 lts in increased H2B ubiquitination, loss of Ataxin-7 results in decreased H2B ubiquitination and H3K

100 nuclear localization signals were mapped to ataxin-7's carboxy-terminal region.

101 s localized to its glutamine-rich region and ataxin-7's Crx binding domain was mapped to its glutamin

102 The ataxin-7/S4 association is modulated by the length of th

103 Loss of SCAANT1 derepressed ataxin-7 sense transcription in a cis-dependent fashion

104 a suggest that the arrestin-like site in the ataxin-7 sequence is a functional phosphate-binding site

105 t signal and nuclear localization signals of ataxin-7, showed increased cellular toxicity.

106 young animals; with increasing age, however, ataxin-7 staining became more pronounced.

107 he presence of the phosphate-binding site in ataxin-7 suggests that this protein may be involved in p

108 CAG repeat encoding a polyglutamine tract in ataxin-7, the SCA7 gene product.

109 RNAs, and introduce silent mutations into an ataxin 7 transgene such that it is resistant to their ef

110 sis of the Crx-ataxin-7 interaction, Crx and ataxin-7 truncation and point mutants were generated, an

111 Wild-type ataxin-7 was barely detectable, as was mutant ataxin-7 i

112 Bergmann glia-specific expression of mutant ataxin-7 was sufficient to produce ataxia and neurodegen

113 thogenesis of SCA7 and possible functions of ataxin-7, we examined the subcellular localization of at

114 ne-rod homeobox protein (CRX) interacts with ataxin-7, we performed further studies to assess this in

115 ear inclusions composed of transgene-derived ataxin-7, which contains a pathogenic polyglutamine expa

116 homologue of the human SCA7-encoded protein ataxin-7, which, in its polyglutamine expanded pathologi

117 Here we develop mirtrons against ataxin 7 with silencing efficacy comparable to shRNAs, a

118 e produced SCA7 transgenic mice that express ataxin-7 with 24 or 92 glutamines in all neurons of the

119 Transgenic mice expressing ataxin-7 with 92 glutamines (92Q) developed a dramatic n

120 ed transgenic mice expressing polyQ-expanded ataxin-7 with a second-site mutation (D266N) to prevent