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

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

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

7 Ataxin-1 (ATXN1) is a ubiquitous polyglutamine protein e

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 In this study, we focus on Ataxin-1 (ATXN1), a dosage-sensitive gene involved in th

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

13 utamine (Q) encoding CAG repeats in the gene Ataxin-1 (ATXN1).

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

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

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

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

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

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

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

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

22 Ataxin-1 ablation in B cells leads to aberrant expressio

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

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

25 ether, we report a immunomodulatory role for ataxin-1 and provide a functional description of the ATX

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

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

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

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

30 -3-3 interacts with phosphorylated wild-type Ataxin-1 but not with the mutants.

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

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

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

34 Mutant forms of ataxin-1 containing expanded glutamine stretches cause t

35 filing link the exaggerated proliferation of ataxin-1 deficient B cells to the activation of extracel

36 expanded polyglutamine (polyQ) tract form of ataxin-1 drives disease progression in spinocerebellar a

37 These findings suggest that loss of ataxin-1 elevates BACE1 expression and Abeta pathology,

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

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

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

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

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

43 e cellular pathways and processes that polyQ-ataxin-1 influences remain poorly understood.

44 Ataxin-1 is a human protein responsible for spinocerebel

45 In SCA1 mice, polyglutamine-expanded mutant ataxin-1 led to the increase of BACE1 post-transcription

46 Here, we investigated the consequences of ataxin-1 loss of function and discovered that knockout o

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

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

49 uclear protein trafficking pathways by polyQ-ataxin-1, a key contribution to furthering understanding

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

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

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

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

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

55 cesses in the presence of elevated levels of ataxin-1.

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

57 mal partners constituting the interactome of ataxin-1[85Q] in Neuro-2a cells, pathways analyses indic

58 calisation of transporters and/or cargoes to ataxin-1[85Q] nuclear bodies.

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

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

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

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

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

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

65 Ataxin 2 intermediate-length polyglutamine (polyQ) expan

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

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

68 hatase 1 regulatory subunit 36 (PPP1R36) and ataxin 2 like (ATXN2L) in three new biological replicate

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

90 -43, FUS (fused in sarcoma), angiogenin, and ataxin-2 in amyotrophic lateral sclerosis; ataxin-2 in s

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

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

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

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

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

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

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

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

99 Yeast ataxin-2, also known as Pbp1 (polyA binding protein-bind

100 Yeast ataxin-2, also known as Pbp1, senses the activity state

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

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

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

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

105 quitin-dependent unfoldase/segregase and the Ataxin 3 (ATX3) deubiquitinase, which together form a ph

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

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

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

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

110 5 mice with citalopram significantly reduced ataxin 3 neuronal inclusions and astrogliosis, rescued d

111 1 and SER-4 were strong genetic modifiers of ataxin 3 neurotoxicity and necessary for therapeutic eff

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

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

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

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

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

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

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

119 (encoding glutamine) repeat expansion in the Ataxin-3 (ATXN3) gene.

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

121 stretch and could lower the level of mutant ataxin-3 (ATXN3), another disease-causing protein with a

122 amine disease proteins, huntingtin (HTT) and ataxin-3 (ATXN3).

123 A concomitant decrease in Ataxin-3 activity facilitates CBP ubiquitination and deg

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

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

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

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

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

129 glutamine repeat leads to a stabilization of ataxin-3 and that ataxin-3 isoforms differ in their aggr

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

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

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

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

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

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

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

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

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

139 steine proteases, are important mediators of ataxin-3 cleavage and implicated in multiple neurodegene

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

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

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

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

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

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

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

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

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

149 provide a unique insight into the impact of ataxin-3 domains in SCA3, identify Hsc70-4 as a SCA3 enh

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

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

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

153 -3 isoforms affect not only major aspects of ataxin-3 function but also MJD pathogenesis.

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

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

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

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

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

159 cerebellar atrophy reduction, smaller mutant ataxin-3 inclusions and motor performance improvement.

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

161 Ataxin-3 interacts with the proteasome-associated protei

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

163 ytic fragmentation of polyglutamine-expanded ataxin-3 is a concomitant and modifier of the molecular

164 Ataxin-3 is a deubiquitinating enzyme and the affected p

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

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

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

168 splicing and interactions between different ataxin-3 isoforms affect not only major aspects of ataxi

169 Here, we examined the effects of different ataxin-3 isoforms and of the premature stop codon on ata

170 eads to a stabilization of ataxin-3 and that ataxin-3 isoforms differ in their aggregation properties

171 stop codon alter ataxin-3 stability and that ataxin-3 isoforms differ in their enzymatic deubiquitina

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

173 also found that loss of HCRT neurons in Hcrt-ataxin-3 mice results in a specific 50% decrease in anot

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

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

176 We found that ataxin-3 pathogenicity is saliently controlled by polygl

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

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

179 This mutant ataxin-3 protein affects several cellular pathways, lead

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

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

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

183 6 days old, even if expression of the human ataxin-3 protein is limited to motor neurons.

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

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

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

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

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

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

190 bnormal glutamine over-repetition within the ataxin-3 protein.

191 splicing and the premature stop codon alter ataxin-3 stability and that ataxin-3 isoforms differ in

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

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

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

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

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

197 protein, Hsc70-4, whose reduction diminishes ataxin-3 toxicity in a UIM-dependent manner.

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

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

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

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

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

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

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

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

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

207 veractivation and led to reduced cleavage of ataxin-3 without affecting its aggregation.

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

209 To determine the role of ataxin-3's non-polyglutamine domains in disease, we util

210 isoforms and of the premature stop codon on ataxin-3's physiological function and on main disease me

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

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

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

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

215 us SNPs in ATXN3 cause amino acid changes in ataxin-3, and one of these polymorphisms introduces a pr

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

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

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

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

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

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

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

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

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

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

226 x with RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'

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

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

229 Ataxin-3, the protein responsible for Spinocerebellar at

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

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

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

233 -3-84Q zebrafish swim shorter distances than ataxin-3-23Q zebrafish as early as 6 days old, even if e

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

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

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

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

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

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

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

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

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

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

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

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

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

247 SCA3 is caused by polyglutamine expansion in ataxin-3.

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

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

250 into an expanded polyglutamine tract within ataxin-3.

251 situ by aggregate-associated deubiquitinase ataxin-3.

252 isorder caused by polyglutamine expansion in ataxin-3.

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

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

255 logical and pathophysiological properties of ataxin-3.

256 rupting this interaction decreases levels of ataxin-3.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

289 -7 cleavage site is an important mediator of ataxin-7 neurotoxicity, suggesting that inhibition of ca

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

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

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

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

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