ライフサイエンスコーパス: ataxin

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

26 -3-3 interacts with phosphorylated wild-type Ataxin-1 but not with the mutants.

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

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

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

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

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

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

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

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

35 Ataxin-1 is a human protein responsible for spinocerebel

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

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

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

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

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

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

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

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

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

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

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

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

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

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

50 functional DUE or at the recently identified ataxin 10 (ATX10) origin, which is silent before disease

51 Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutate

52 isposing to ALS and that polyQ expansions in ataxin 2 are a significant risk factor for the disease.

53 lyglutamine (polyQ) expansions (27-33 Qs) in ataxin 2 as a genetic risk factor for sporadic ALS in No

54 h antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNA-binding and

55 Repeats of CAG in the ataxin 2 gene (ATXN2) in the long-normal range (sometime

56 Ataxin 2 intermediate-length polyglutamine (polyQ) expan

57 results provide mechanistic insight into how ataxin 2 intermediate-length polyQ expansions could cont

58 BP1, are a known ALS genetic risk factor and ataxin 2 is a stress granule component in mammalian cell

59 Our findings support the hypothesis that ataxin 2 plays an important role in predisposing to ALS

60 Because longer ataxin 2 polyQ expansions are associated with a differen

61 Here, we show that intermediate-length ataxin 2 polyQ expansions enhance stress-induced TDP-43

62 We also connect intermediate-length ataxin 2 polyQ expansions to the stress-dependent activa

63 triking association with ALS cases harboring ataxin 2 polyQ expansions.

64 ical feature of ALS with intermediate-length ataxin 2 polyQ expansions.

65 Thus, intermediate-length ataxin 2 polyQ repeat expansions are associated with inc

66 To extend these findings, we assessed the ataxin 2 polyQ repeat length in 1294 European ALS patien

67 we report functional analysis of Drosophila Ataxin 2-binding protein 1 (A2BP1) during this process.

68 pends on the Drosophila homolog of the human ataxin 2-binding protein 1 (A2BP1) gene.

69 We show that Fox-1/Ataxin 2-Binding Protein 1 (A2BP1), a protein implicated

70 gile X mental retardation protein (FMRP) and Ataxin-2 (Atx2) are triplet expansion disease- and stres

71 We found that ATAXIN-2 (ATX2), an RNA-associated protein involved in n

72 We found that the Drosophila homolog of ATAXIN-2 (ATX2)--an RNA-binding protein implicated in hu

73 lutamine) expansion in the cytosolic protein ataxin-2 (Atx2).

74 olyglutamine tracts in the cytosolic protein ataxin-2 (Atx2).

75 Ataxin-2 (ATXN2) homologs exist in all eukaryotic organi

76 Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia ty

77 ing the binding of 2 of its client proteins, ataxin-2 and Sf3b2.

78 oteins implicated in neurodegeneration (i.e. Ataxin-2 and SMN) interact with stress granules.

79 ndians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associa

80 ponent of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic

81 diate-length polyglutamine expansions in the ataxin-2 gene increase risk of ALS.

82 -43, FUS (fused in sarcoma), angiogenin, and ataxin-2 in amyotrophic lateral sclerosis; ataxin-2 in s

83 d ataxin-2 in amyotrophic lateral sclerosis; ataxin-2 in spinocerebellar ataxia; and SMN (survival of

84 First, we crossed ataxin-2 knockout mice with TDP-43 (also known as TARDBP

85 this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functi

86 endent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model

87 The decrease in ataxin-2 reduced aggregation of TDP-43, markedly increas

88 A decrease in ataxin-2 suppresses TDP-43 toxicity in yeast and flies,

89 ble approach, we administered ASOs targeting ataxin-2 to the central nervous system of TDP-43 transge

90 the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90

91 ns associated with ALS, including TDP-43 and ataxin-2, is that they localize to stress granules.

92 d by the conserved RNA-binding protein ATX-2/Ataxin-2, which targets and maintains ZEN-4 at the spind

93 ues, similar to the expression of endogenous ataxin-2.

94 tic strategy for ALS that involves targeting ataxin-2.

95 f three members of the Josephin family DUBs: ataxin 3 (ATXN3), ataxin 3-like (ATXN3L) and Josephin do

96 This activity of ataxin 3 and its polyQ-mediated interaction with beclin

97 ch as huntingtin in Huntington's disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3).

98 her polyQ disease proteins, including mutant ataxin 3 itself.

99 5 mice with citalopram significantly reduced ataxin 3 neuronal inclusions and astrogliosis, rescued d

100 1 and SER-4 were strong genetic modifiers of ataxin 3 neurotoxicity and necessary for therapeutic eff

101 show that the polyQ domain enables wild-type ataxin 3 to interact with beclin 1, a key initiator of a

102 action allows the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome-mediated de

103 such protein is the deubiquitinating enzyme ataxin 3, which is widely expressed in the brain.

104 ing a Caenorhabditis elegans model of mutant ataxin 3-induced neurotoxicity.

105 the Josephin family DUBs: ataxin 3 (ATXN3), ataxin 3-like (ATXN3L) and Josephin domain containing 1

106 ne mRNA allele encoding huntingtin (HTT) and ataxin-3 (ATX-3) proteins.

107 rom expansion of the polyglutamine domain in ataxin-3 (Atx3).

108 order caused by a polyglutamine expansion in ataxin-3 (ATX3; MJD1) protein.

109 eads to misfolding and aggregation of mutant ataxin-3 (ATXN3) and degeneration of select brain region

110 expanded CAG repeats within an allele of the ataxin-3 (ATXN3) and huntingtin (HTT) genes, respectivel

111 The physiological function of Ataxin-3 (ATXN3), a deubiquitylase (DUB) involved in Mac

112 n whereby ubiquitination at Lys-117 enhances ataxin-3 activity independent of the known ubiquitin-bin

113 crease local structural fluctuations to slow ataxin-3 aggregation.

114 For example, polyglutamine expansion in ataxin-3 allosterically triggers the aggregation of the

115 Although ataxin-3 and ATXN3L adopt similar folds, they bind ubiqu

116 AG repeats can preferentially inhibit mutant ataxin-3 and HTT protein expression in cultured cells.

117 ophagy pathway prevents the removal of human ataxin-3 and improved movement produced by calpeptin tre

118 pathways mediated by polyglutamine-expanded ataxin-3 and that phosphorylation of this residue protec

119 These findings establish ataxin-3 as a novel DUB that edits topologically complex

120 also increased the levels of polyQ-expanded ataxin-3 as well as mutant alpha-synuclein and superoxid

121 icate that ubiquitin-dependent activation of ataxin-3 at Lys-117 is important for its ability to redu

122 re, we report that ubiquitination of the DUB ataxin-3 at lysine residue 117, which markedly enhances

123 Mutations were made in ataxin-3 at selected positions, introducing the correspo

124 Ataxin-3 binds both Lys(48)- or Lys(63)-linked chains ye

125 four proteins, Parkin acted on nNOS and Q78 ataxin-3 but not on the steroid receptors, and Mdm2 did

126 The protein ataxin-3 carries a polyglutamine stretch close to the C-

127 Mutant ataxin-3 caused an evolving neuronal dysfunction (loss o

128 olyQ) repeat expansion in the deubiquitinase ataxin-3 causes neurodegeneration in Spinocerebellar Ata

129 Polyglutamine repeat expansion in ataxin-3 causes neurodegeneration in the most common dom

130 caspase-site mutant proteins indicates that Ataxin-3 cleavage enhances neuronal loss in vivo.

131 n-3-23Q and develop ataxin-3 neuropathology, ataxin-3 cleavage fragments and motor impairment.

132 bitor compound calpeptin decreased levels of ataxin-3 cleavage fragments, but also removed all human

133 However, the pathological significance of Ataxin-3 cleavage has not been carefully examined.

134 ivo confirmation of the pathological role of Ataxin-3 cleavage indicates that therapies targeting Ata

135 cleavage indicates that therapies targeting Ataxin-3 cleavage might slow disease progression in SCA3

136 To gain insight into the significance of Ataxin-3 cleavage, we developed a Drosophila SL2 cell-ba

137 Ataxin-3 cleaves ubiquitin chains through its amino-term

138 a potential target through which to enhance ataxin-3 degradation for SCA3 therapy.

139 bility of two juxtaposed helices critical to ataxin-3 deubiquitinase activity.

140 Upon completion of substrate ubiquitination, ataxin-3 deubiquitinates CHIP, effectively terminating t

141 in and onto ataxin-3, further explaining how ataxin-3 deubiquitination is coupled to parkin ubiquitin

142 he strain expressing full-length, functional ataxin-3 displayed persistent upregulation of enzymes in

143 significantly more efficient enzyme than the ataxin-3 domain despite their sharing 85% sequence ident

144 nt to increase the catalytic activity of the ataxin-3 domain to levels comparable with that of ATXN3L

145 ed in the yeast Pichia pastoris, full-length ataxin-3 enabled almost normal growth at 37 degrees C, w

146 ss-siRNAs are allele-selective inhibitors of ataxin-3 expression and then redesign ss-siRNAs to optim

147 anisms that protect Josephin and nonexpanded ataxin-3 from aberrant aggregation.

148 ting the autoprotective role that pathogenic ataxin-3 has against itself, which depends on the co-cha

149 parable with that of ATXN3L, suggesting that ataxin-3 has been subject to evolutionary restraints tha

150 mice with lentiviral vectors encoding mutant ataxin-3 in one hemisphere and wild-type ataxin-3 in the

151 d, suggesting that the cellular functions of ataxin-3 in protein quality control are modulated throug

152 ant ataxin-3 in one hemisphere and wild-type ataxin-3 in the other hemisphere (as internal control).

153 ), an E3 ubiquitin ligase that ubiquitinates ataxin-3 in vitro, is dispensable for its ubiquitination

154 ) associated with increased number of mutant ataxin-3 inclusions in the basal ganglia.

155 In cells, ubiquitination of endogenous ataxin-3 increases when the proteasome is inhibited, whe

156 Ataxin-3 interacts with the proteasome-associated protei

157 We report here that ataxin-3 interferes with the attachment of ubiquitin (Ub

158 es pathology in animals, we investigated how ataxin-3 is degraded.

159 ng and aggregation of the Josephin domain of ataxin-3 is implicated in spinocerebellar ataxia-3.

160 We report that S12 of ataxin-3 is phosphorylated in neurons and that mutating

161 Ataxin-3 is the first reported DUB in which ubiquitinati

162 or chloroquine blocked the decrease in human ataxin-3 levels and the improved movement produced by ca

163 activity in wild-type mice but not in orexin/ataxin-3 mice in which the Hcrt neurons degenerate postn

164 ranscripts that were decreased in transgenic ataxin-3 mice that were normalized following temsirolimu

165 Orexin/ataxin-3 mice, in which the Hcrt neurons degenerate, did

166 vival compared with ataxin-3-23Q and develop ataxin-3 neuropathology, ataxin-3 cleavage fragments and

167 suggest that functional pairing of E3s with ataxin-3 or similar DUBs represents an important point o

168 other modifiers of the pathogenic, expanded Ataxin-3 polyQ protein could also modify the CAG-repeat

169 eavage fragments, but also removed all human ataxin-3 protein (confirmed by ELISA) and prevented the

170 We identified that this clearance of ataxin-3 protein by calpeptin treatment resulted from an

171 Our data indicate that Ataxin-3 protein cleavage is conserved in the fly and ma

172 anio rerio) model of MJD by expressing human ataxin-3 protein containing either 23 glutamines (23Q, w

173 6 days old, even if expression of the human ataxin-3 protein is limited to motor neurons.

174 Mutating UbS2 decreases ataxin-3 protein levels in cultured mammalian cells and

175 Ataxin-3 protein with an expanded polyglutamine (polyQ)

176 calpeptin produces complete removal of human ataxin-3 protein, due to induction of the autophagy qual

177 that induction of autophagy, and removal of ataxin-3 protein, plays an important role in the protect

178 anded polyglutamine (polyQ) tract within the Ataxin-3 protein.

179 f the polyglutamine repeat region within the ataxin-3 protein.

180 lating into a polyglutamine tract within the ataxin-3 protein.

181 and in Drosophila results in lower levels of ataxin-3 protein.

182 Ataxin-3 shows even greater activity toward mixed linkag

183 Our work also suggests that ataxin-3 suppresses degeneration by regulating toxic pro

184 red with ataxin-3 with only Lys-117 present, ataxin-3 that does not become ubiquitinated performs sig

185 ve in this model of MJD and removal of human ataxin-3 through macro-autophagy plays an important role

186 n at Lys-117 also facilitates the ability of ataxin-3 to induce aggresome formation in cells.

187 y of a number of proteins that interact with Ataxin-3 to modulate SCA3 pathogenicity using Drosophila

188 e compared to wild-type mice, whereas orexin/ataxin-3 transgenic mice showed an intermediate 28% incr

189 these systems in 6 wild-type mice, 6 orexin/ataxin-3 transgenic mice, and 5 orexin ligand knockout m

190 was delivered into the brains of the orexin-ataxin-3 transgenic mouse model of human narcolepsy.

191 ockout mice and orexin neuron-ablated orexin/ataxin-3 transgenic rats.

192 Notably, mutant ataxin-3 triggered early synaptotoxicity (decreased syna

193 Here we show that, unlike most proteins, ataxin-3 turnover does not require its ubiquitination, b

194 Ataxin-3 was found to counteract parkin self-ubiquitinat

195 In vitro studies revealed that inactive ataxin-3 was more slowly degraded by the proteasome and

196 Unexpectedly, pathogenic ataxin-3 with a mutated Rad23-binding site at UbS2, desp

197 Compared with ataxin-3 with only Lys-117 present, ataxin-3 that does n

198 Ataxin-3's degradation is inhibited by its binding to th

199 ssociated E3 ubiquitin-ligase interacts with ataxin-3, a deubiquitinating enzyme associated with Mach

200 Ataxin-3, a deubiquitinating enzyme, is the disease prot

201 uitination directly enhances the activity of ataxin-3, a DUb implicated in protein quality control an

202 We further show that ataxin-3, a p97-associated deubiquitinating enzyme previ

203 so directly regulates the activity of a DUB, ataxin-3, a polyglutamine disease protein implicated in

204 disease (MJD), also known as spinocerebellar ataxin-3, affects neurons of the brain and spinal cord,

205 parkin required the catalytic cysteine 14 in ataxin-3, although the precise mechanism remained unclea

206 substrate, the polyglutamine disease protein ataxin-3, and showed that Ube2w can ubiquitinate a lysin

207 show that the polyglutamine disease protein, ataxin-3, binds and cleaves ubiquitin chains in a manner

208 on enhances ubiquitin (Ub) chain cleavage by ataxin-3, but does not alter its preference for K63-link

209 ermining solubility and aggregation rates of ataxin-3, but these properties are profoundly modulated

210 s Rad23 increases the toxicity of pathogenic ataxin-3, coincident with increased levels of the diseas

211 e N terminus of unmodified and ubiquitinated ataxin-3, demonstrating that Ube2w attaches ubiquitin to

212 Expanded ataxin-3, for example, is more neurotoxic in fruit fly m

213 the E2 is diverted away from parkin and onto ataxin-3, further explaining how ataxin-3 deubiquitinati

214 Finally, expression of the disease protein, ataxin-3, in transfected cells increases the inactivatio

215 dent of the known ubiquitin-binding sites in ataxin-3, most likely through a direct conformational ch

216 e specialized deubiquitinating enzyme (DUB), ataxin-3, participate in initiating, regulating, and ter

217 rom the activity of deubiquitinases, such as ataxin-3, that are necessary for efficient ERAD.

218 ound in four human deubiquitinating enzymes: ataxin-3, the ataxin-3-like protein (ATXN3L), Josephin-1

219 Mutant ataxin-3, the genetic cause of Machado-Joseph Disease, a

220 Here, we show that ataxin-3, the protein involved in spinocerebellar ataxia

221 Ataxin-3, the protein responsible for Spinocerebellar at

222 implications for the function of parkin and ataxin-3, two proteins responsible for closely related n

223 spinocerebellar ataxia type 3 (SCA3) protein ataxin-3, we isolated an upregulation allele of musclebl

224 stabilizes the interaction between CHIP and ataxin-3, which through its DUB activity limits the leng

225 decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels rema

226 rafish have decreased survival compared with ataxin-3-23Q and develop ataxin-3 neuropathology, ataxin

227 -3-84Q zebrafish swim shorter distances than ataxin-3-23Q zebrafish as early as 6 days old, even if e

228 ebrafish (male and female) revealed that the ataxin-3-84Q zebrafish have decreased survival compared

229 Ataxin-3-84Q zebrafish swim shorter distances than ataxi

230 Treating the EGFP-ataxin-3-84Q zebrafish with the calpain inhibitor compou

231 Importantly, reducing Rad23 suppresses ataxin-3-dependent degeneration in flies.

232 Moreover, ataxin-3-dependent deubiquitination of parkin required t

233 The mechanism involves an ataxin-3-dependent stabilization of the complex between

234 d by beclin 1, was particularly inhibited in ataxin-3-depleted human cell lines and mouse primary neu

235 ld(S) VCP-binding domain with an alternative ataxin-3-derived VCP-binding sequence restores its prote

236 rats stereotaxically injected with expanded ataxin-3-encoding lentiviral vectors, mutation of serine

237 uman deubiquitinating enzymes: ataxin-3, the ataxin-3-like protein (ATXN3L), Josephin-1, and Josephin

238 narcolepsy models: Hcrt (orexin) knockouts, ataxin-3-orexin, and doxycycline-controlled-diphtheria-t

239 we tested whether genetically modulating the ataxin-3-Rad23 interaction regulates its toxicity in Dro

240 nd potentially therapeutic properties of the ataxin-3-Rad23 interaction; they highlight this interact

241 We found that adult orexin/ataxin-3-transgenic (AT) mice, in which Hcrt neurons deg

242 a lysine-less, but not N-terminally blocked, ataxin-3.

243 into an expanded polyglutamine tract within ataxin-3.

244 situ by aggregate-associated deubiquitinase ataxin-3.

245 isorder caused by polyglutamine expansion in ataxin-3.

246 f ubiquitination in wild type and pathogenic ataxin-3.

247 e molecular mechanism whereby this occurs in ataxin-3.

248 K48-specific avidity in a different protein, ataxin-3.

249 o-expressed with the GR, nNOS, AR112Q or Q78 ataxin-3.

250 rupting this interaction decreases levels of ataxin-3.

251 lyubiquitin chains by the Josephin domain of ataxin-3.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

287 -7 cleavage site is an important mediator of ataxin-7 neurotoxicity, suggesting that inhibition of ca

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

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

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

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

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

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

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

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

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

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

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

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

300 ful suppressor of Wallerian degeneration and ataxin- and tau-induced neurodegeneration in flies and m