ライフサイエンスコーパス: ataxin-1

1 glutamine repeat within the disease protein, ataxin 1.

2 ntly modify the polyglutamine repeat protein ataxin-1.

3 ndent on the continuous expression of mutant ataxin-1.

4 resence of the polyglutamine repeat protein, ataxin-1.

5 bility to repair the damage caused by mutant ataxin-1.

6 ally long polyglutamine tract in the protein ataxin-1.

7 of a polyglutamine tract in the gene product ataxin-1.

8 d the crystal structure of the AXH domain of ataxin-1.

9 eat that encodes the amino acid glutamine in ataxin-1.

10 amine tract alters the folding properties of ataxin-1.

11 polyglutamine tract within the SCA1 product, ataxin-1.

12 rther demonstrating that A1Up interacts with ataxin-1.

13 sion of a polyglutamine tract in the protein ataxin-1.

14 unrelated glutamine-repeat disease protein, ataxin-1.

15 sed by expansion of a polyglutamine tract in ataxin-1.

16 hat are fewer in number than those of normal ataxin-1.

17 lutamine tract within the SCA1 gene product, ataxin-1.

18 which encodes glutamine in the novel protein ataxin-1.

19 ing that sacsin is protective against mutant ataxin-1.

20 d sacsin knockdown on polyglutamine-expanded ataxin-1.

21 can partially reverse cytotoxicity caused by ataxin-1.

22 which largely abrogates the cytotoxicity of ataxin-1.

23 x involved in neuron survival as a target of ataxin-1.

24 interacts with and ubiquitinates unexpanded ataxin-1.

25 amine repeat within the SCA1-encoded protein ataxin-1.

26 phosphorylation of both wild-type and mutant ataxin-1.

27 While ataxin-1 [2Q] and mutant ataxin-1 [92Q] are polyubiquiti

28 ife of A1Up, whereas nonpathogenic wild-type ataxin-1-(30Q) or ataxin-1-(82Q)-A776 did not.

29 with those seen in two non-ataxic lines, A02-ataxin-1[30Q] and K772T-[82Q], nine genes were identifie

30 siRNA did not affect cell viability with GFP-ataxin-1[30Q], but enhanced the toxicity of GFP-ataxin-1

31 , restored SUMO levels to those of wild-type ataxin-1[30Q].

32 In a second series of transgenic mice, ataxin-1[77] containing a deletion within the self-assoc

33 aggregation in pathogenesis, mice expressing ataxin-1[82] with a mutated NLS were established.

34 as a cellular model to assess stress due to ataxin-1 82Q protein expression and determine whether NP

35 Furthermore, when ataxin-1 82Q was expressed in 15-lipoxygenase-1-deficien

36 gly, the interaction between A1Up and mutant ataxin-1-(82Q) increased the half-life of A1Up, whereas

37 as nonpathogenic wild-type ataxin-1-(30Q) or ataxin-1-(82Q)-A776 did not.

38 The previous finding that mutant ataxin-1[82Q] disrupted promyelocytic leukemia (PML) onc

39 76 appeared to affect cellular deposition of ataxin-1[82Q] in that ataxin-1[82Q]-A776 failed to form

40 ataxin-1[82Q] redistributed Sp100 to mutant ataxin-1[82Q] nuclear inclusions.

41 Similar to the PML protein, mutant ataxin-1[82Q] redistributed Sp100 to mutant ataxin-1[82Q

42 rn of gene expression in the SCA1 ataxic B05-ataxin-1[82Q] transgenic mouse line with those seen in t

43 xin-1[30Q], but enhanced the toxicity of GFP-ataxin-1[82Q], suggesting that sacsin is protective agai

44 cellular deposition of ataxin-1[82Q] in that ataxin-1[82Q]-A776 failed to form nuclear inclusions in

45 hin Purkinje cell nuclei, yet the ability of ataxin-1[82Q]-A776 to induce disease was substantially r

46 uced pathogenesis was examined by generating ataxin-1[82Q]-A776 transgenic mice.

47 These mice expressed ataxin-1[82Q]-A776 within Purkinje cell nuclei, yet the

48 The phospho-mutant, ataxin-1[82Q]-S776A, restored SUMO levels to those of wi

49 resence of the expanded polyglutamine tract, ataxin-1[82Q].

50 While ataxin-1 [2Q] and mutant ataxin-1 [92Q] are polyubiquitinated equally well in vit

51 t into the function of the SCA1 gene product ataxin-1, a novel protein without homology to previously

52 of SCA1 patients and transgenic mice, mutant ataxin-1 accumulates in a single, ubiquitin-positive nuc

53 However, no evidence of nuclear ataxin-1 aggregates was found.

54 Inhibiting proteasomal degradation promotes ataxin-1 aggregation in transfected cells.

55 while determined by polyglutamine expansion, ataxin-1 aggregation is noticeably reduced by deletion o

56 Essential for ataxin-1 aggregation is the anomalous expansion of a pol

57 SDJ in HeLa cells decreases the frequency of ataxin-1 aggregation.

58 We suggest that S776 of ataxin-1 also has a critical role in SCA1 pathogenesis.

59 xamine whether stopping expression of mutant ataxin-1 alters the disease phenotype.

60 DP-43 itself, FUS/TLS, progranulin, Tau, and ataxin 1 and -2.

61 Here, we show that ataxin 1 and ataxin 3 proteins are recruited into aggreg

62 is modulated by subcellular distribution of ataxin-1 and by components of the protein folding/degrad

63 re regulated, we examined phosphorylation of ataxin-1 and found that serine 776 (S776) was phosphoryl

64 Boat and ataxin-1 share a conserved AXH (ataxin-1 and HMG-box protein 1) domain, which is essenti

65 CAG repeat within the coding regions of the Ataxin-1 and Huntingtin proteins, respectively.

66 pathways responsible for differences between Ataxin-1 and Huntingtin-induced neurodegeneration.

67 The features of the interaction between ataxin-1 and LANP, their spatial and temporal patterns o

68 thology are phosphorylation of serine 776 in Ataxin-1 and nuclear localization of the protein.

69 heir downregulation was mediated by expanded ataxin-1 and occurred before detectable pathology.

70 r the transcriptional repression activity of ataxin-1 and participates in protein aggregation.

71 at SCA1 is not caused by loss of function of ataxin-1 and point to the possible role of ataxin-1 in l

72 Using wild-type Ataxin-1 and Ser776 mutants to a phosphomimetic aspartat

73 escent cells, causing rapid decay of targets Ataxin-1 and Snurportin-1, and preventing premature sene

74 their respective ubiquitination substrates, Ataxin-1 and Snurportin-1.

75 state levels of both expanded and unexpanded ataxin-1 and suppresses their toxicity.

76 The binding of both ataxin-1 and the androgen receptor to GAPDH does not var

77 relevance for the aggregation properties of ataxin-1 and thus for disease.

78 proteotoxic stress due to abnormally folded ataxin-1, and 2) NPD1 promotes cell survival through mod

79 related proteins (polyglutamine, huntingtin, ataxin-1, and superoxide dismutase-1) inhibits clathrin-

80 The murine and human ataxin-1 are highly homologous but the CAG repeat is vir

81 otoxicity nor the transcriptional targets of ataxin-1 are known.

82 Mice lacking ataxin-1 are viable, fertile, and do not show any eviden

83 Nuclear matrix preparations demonstrate that ataxin-1 associates with the nuclear matrix in Purkinje

84 78 glutamines, prolonged exposure to mutant ataxin-1 at endogenous levels is necessary to produce a

85 polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutam

86 Ataxin 1 (Atx1) is a foci-forming polyglutamine protein

87 We discuss the paradigmatic example of ataxin-1 (Atx1), the protein responsible for neurodegene

88 Ataxin 1 (Atxn1) is a protein of unknown function associ

89 Ataxin 1 (ATXN1) is one of these four AD candidate genes

90 This appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional represso

91 sed by expansion of a polyglutamine tract in ataxin 1 (ATXN1).

92 expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1).

93 reviously that partial suppression of mutant ataxin-1 (ATXN1) expression, using virally expressed RNA

94 xpansion of a polyglutamine tract within the ataxin-1 (ATXN1) protein.

95 , the expanded polyglutamine tract is in the ataxin-1 (ATXN1) protein.

96 To further investigate the ability of ataxin-1 (ATXN1) to impact CF/PC innervation, this study

97 d by expansion of a translated CAG repeat in Ataxin-1 (ATXN1).

98 CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1).

99 by expansion of a glutamine repeat tract in ataxin-1 (ATXN1).

100 ic glutamine repeat expansion in the protein ataxin-1 (ATXN1).

101 caused by expansion of a glutamine tract in ataxin-1 (ATXN1).

102 tract in the disease protein, in this case, ATAXIN-1 (ATXN1).

103 ansmission required expression of pathogenic ataxin-1 (ATXN1[82Q]) and for its entrance into the nucl

104 We show that ataxin-1 binds specifically to histone deacetylase-4 (HD

105 sociation with a related protein, Brother of ataxin-1 (Boat).

106 CHIP promotes ubiquitination of expanded ataxin-1 both in vitro and in cell culture.

107 in mice, Purkinje cells that express mutant ataxin-1 but not a ubiquitin-protein ligase have signifi

108 -3-3 interacts with phosphorylated wild-type Ataxin-1 but not with the mutants.

109 tory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby

110 er, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and

111 Here we show that high levels of wild-type ataxin-1 can cause degenerative phenotypes similar to th

112 Finally, NPD1 signaling interfered with ataxin-1/capicua repression of gene expression and decre

113 Colocalization studies show that mutant ataxin-1 causes a specific redistribution of the nuclear

114 Expansion of a polyglutamine tract within ataxin-1 causes spinocerebellar ataxia type 1 (SCA1).

115 nomalous expansion of a polymorphic tract in Ataxin-1 causes the autosomal dominant spinocerebellar a

116 cence studies demonstrate that both LANP and ataxin-1 colocalize in nuclear matrix-associated subnucl

117 ling modulates formation or stabilization of ataxin-1 complexes.

118 imilarly, HeLa cells transfected with mutant ataxin-1 develop nuclear aggregates which colocalize wit

119 first time that inclusions such as those of ataxin-1 disperse during mitosis, thus reducing the nucl

120 nic domains prompted us to determine whether ataxin-1 disrupts another component of PML oncogenic dom

121 vitro RNA-binding assay, we demonstrate that ataxin-1 does bind RNA and that this binding diminishes

122 This analysis revealed that ataxin-1 does have the ability to self-associate, howeve

123 dentified NBA (N-terminal region of Boat and ataxin-1) domain.

124 Ectopic ataxin-1 expression induced RPE cell apoptosis, which wa

125 In this assay, ataxin-1 expression was monitored by enhanced green fluo

126 city induced by mutant huntingtin and mutant ataxin-1 expression.

127 d data demonstrate that wild type and mutant ataxin-1 form homo and heterodimers.

128 survival through modulating stabilization of ataxin-1 functional complexes and pro-/antiapoptotic and

129 n the nucleus, A1Up co-localized with mutant ataxin-1, further demonstrating that A1Up interacts with

130 escence in cell lines stably expressing EGFP-ataxin-1 fusion protein.

131 used by an expanded glutamine tract in human Ataxin-1 (hAtx-1).

132 ated reduced staining for both PKC gamma and ataxin 1 in Purkinje cells, whereas staining for calbind

133 e-induced neurodegeneration caused by mutant ataxin-1 in a mouse model of SCA1.

134 te and to alanine, we show that U2AF65 binds Ataxin-1 in a Ser776 phosphorylation independent manner

135 gene expression and decreased phosphorylated ataxin-1 in an Akt-independent manner, suggesting that N

136 f ataxin-1 and point to the possible role of ataxin-1 in learning and memory.

137 is not essential for the normal function of ataxin-1 in mice.

138 Overexpression of mutant ataxin-1 in Purkinje cells of transgenic mice results in

139 protein encoded by the SCA1 gene) and mutant ataxin-1 in the Purkinje cells of transgenic mice.

140 ne increases CHIP-mediated ubiquitination of ataxin-1 in vitro, and the tetratricopeptide repeat doma

141 on of SCA1[82Q] transgene expression, mutant ataxin-1, including that in nuclear inclusions, was clea

142 ellar morphology and resolved characteristic ataxin-1 inclusions in Purkinje cells of SCA1 mice.

143 Unlike those of a non-pathologic protein, ataxin-1 inclusions were shown to be capable of non-spec

144 NPD1 reduced misfolded ataxin-1-induced accumulation of proapoptotic Bax in the

145 estigate the role of CHIP in protecting from ataxin-1-induced neurodegeneration.

146 collection of genetic modifiers of expanded Ataxin-1-induced neurotoxicity, we performed a comparati

147 yceraldehyde-3-phosphate dehydrogenase as an ataxin-1 interacting protein.

148 The ataxin-1 interacting ubiquitin-like protein (A1Up) conta

149 d the yeast two-hybrid system to identify an ataxin-1-interacting protein, A1Up.

150 ated the physiological relevance of the Boat-ataxin-1 interaction in Drosophila and discovered that a

151 The Boat-ataxin-1 interaction is mediated through multiple region

152 Ataxin-1 is a human protein responsible for spinocerebel

153 Ataxin-1 is a neurodegenerative disorder protein whose g

154 Ataxin-1 is a neurodegenerative disorder protein whose m

155 Ataxin-1 is a polyglutamine protein whose expansion caus

156 the yeast two hybrid system to determine if ataxin-1 is capable of multimerization.

157 Here, we observed that ataxin-1 is degraded by the ubiquitin-proteasome pathway

158 report here that the cytotoxicity caused by ataxin-1 is modulated by association with a related prot

159 Thus, although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 i

160 taxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in tra

161 rine 776 (S776) of both wild-type and mutant ataxin-1 is phosphorylated in vivo and in vitro.

162 The interaction between LANP and ataxin-1 is significantly stronger when the number of gl

163 enerated a targeted duplication of the mouse ataxin-1-like (Atxn1l, also known as Boat) locus, a high

164 rodegenerative disorder, develop ataxia with ataxin-1 localized to aggregates within cerebellar Purki

165 tely 0.5 microm across, whereas the expanded ataxin-1 localizes to a single approximately 2-microm st

166 Mutant ataxin-1 localizes to a single nuclear structure in affe

167 Normal ataxin-1 localizes to several nuclear structures approxi

168 We found that ataxin-1 localizes to the nuclei of cerebellar Purkinje

169 t impaired proteasomal degradation of mutant ataxin-1 may contribute to SCA1 pathogenesis.

170 Evidence suggests that ataxin-1 may function as a transcription repressor.

171 ddition, these data support the concept that ataxin-1 may function in the formation and regulation of

172 e that toxicity of the polyglutamine protein Ataxin-1 may not be due to abberant protein interactions

173 n in Drosophila and discovered that a mutant ataxin-1-mediated eye defect is suppressed by ataxin-1's

174 ine 776 is also crucial for selection of the Ataxin-1 multiple partners.

175 ttern of nuclear localization; with expanded ataxin-1 occurring in larger structures that are fewer i

176 Mice homozygous for mutant ataxin-1 on a C57BL/6J-129/SvEv mixed background perform

177 inclusions formed by polyglutamine-expanded ataxin-1 or huntingtin.

178 antly in purkinje cells, the primary site of ataxin-1 pathology.

179 to aid in elucidating the biological role of ataxin-1 phosphorylation and perhaps provide potential l

180 /Akt pathway predominantly diminished mutant ataxin-1 phosphorylation.

181 These observations suggest that ataxin-1 plays a role in RNA metabolism and that the exp

182 ipper mediated multimerization involving the ataxin-1 polyglutamine tract.

183 We find that CHIP and ataxin-1 proteins directly interact and co-localize in N

184 3 cooperate to modulate the neurotoxicity of ataxin-1 provides insight into SCA1 pathogenesis and ide

185 deficits and anatomical changes observed in ataxin-1[Q80] transgenic lines, ataxin-2[Q58] remained c

186 f these interactions, we show that wild type ataxin-1 represses MEF2-dependent transcription, whereas

187 es of a third polyglutamine disease protein, ataxin-1, reveal unexpected heterogeneity in the dynamic

188 taxin-1-mediated eye defect is suppressed by ataxin-1's association with Boat.

189 pecific antibody (PN1168) was used to assess ataxin-1 S776 phosphorylation.

190 he involvement of the polyglutamine tract in ataxin-1 self-association, and instead localized the mul

191 These results, while identifying an ataxin-1 self-interaction region, fail to support a prop

192 suggest a novel pathogenic mechanism whereby ataxin-1 sequesters and inhibits the neuronal survival f

193 Boat and ataxin-1 share a conserved AXH (ataxin-1 and HMG-box pro

194 1 cells transfected with wild-type or mutant ataxin-1 show a similar pattern of nuclear localization;

195 Mutant ataxin-1 solubility varied with brain region, being most

196 The phospho-S776 ataxin-1 specific antibody (PN1168) was used to assess a

197 There was a decrease in ataxin-1 SUMOylation in the presence of the expanded pol

198 Ataxin-1 SUMOylation was mapped to at least five lysine

199 group domain, and Lys(746) all contribute to ataxin-1 SUMOylation.

200 e disease caused by the expression of mutant ataxin-1 that contains an expanded polyglutamine tract.

201 subcellular localization of wild-type human ataxin-1 (the protein encoded by the SCA1 gene) and muta

202 genic mice that overexpress the normal human ataxin-1 (the SCA1[30Q] line) and wild-type controls.

203 genic mice that overexpress the mutant human ataxin-1 (the SCA1[82Q] line) were measured longitudinal

204 A region in ataxin-1, the AXH domain, exhibits significant sequence

205 Mutant ataxin-1, the expanded polyglutamine protein causing spi

206 d to identify putative functional domains in ataxin-1, the murine homolog (Sca1) was isolated.

207 Here, we show that the AXH domain of ataxin-1, the protein involved in spinocerebellar ataxia

208 was based on the observation that LANP binds ataxin-1, the protein involved in this disease, in a glu

209 investigated whether polyglutamine-expanded ATAXIN-1, the protein that underlies spinocerebellar ata

210 In this study we used ataxin-1, the SCA1 gene product, as a bait in the yeast

211 acidic nuclear protein (LANP) interacts with ataxin-1, the SCA1 gene product.

212 ty of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation.

213 fied by SUMO, we investigated the ability of ataxin-1 to be SUMOylated.

214 strated that in order for a mutant allele of ataxin-1 to cause disease it must be transported to the

215 lutamine tract expansion and localization of ataxin-1 to the nucleus of Purkinje cells are not suffic

216 ntify the MEF2-HDAC4 complex as a target for ataxin-1 transcriptional repression activity and suggest

217 nteractions with chaperones, is required for ataxin-1 ubitiquination in cell culture.

218 Physical interaction between GAPDH and ataxin-1 was also demonstrated in vitro.

219 SUMOylation of ataxin-1 was dependent on a functional nuclear localizat

220 pathways leading to S776 phosphorylation of ataxin-1, we developed a cell-culture based assay to scr

221 e lines, each expressing a different form of ataxin-1, we utilized a strategy that resulted in the id

222 s that Boat is an in vivo binding partner of ataxin-1 whose altered expression in Purkinje cells may

223 The association of ataxin-1 with 14-3-3 is regulated by Akt phosphorylation

224 cific, as it occurs with mHtt but not mutant ataxin-1 with expanded polyQ.

225 at toxicity is solely due to interactions of Ataxin-1 with its normal binding partners.

226 These results suggest that A1Up may link ataxin-1 with the chaperone and ubiquitin-proteasome pat

227 T for an in cell study of the interaction of Ataxin-1 with the spliceosome-associated U2AF65 and the