ライフサイエンスコーパス: ataxin-3

1 to a pathogenic length of 78 glutamines (Q78 ataxin-3).

2 into an expanded polyglutamine tract within ataxin-3.

3 situ by aggregate-associated deubiquitinase ataxin-3.

4 isorder caused by polyglutamine expansion in ataxin-3.

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

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

7 logical and pathophysiological properties of ataxin-3.

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

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

10 le is known about the cellular regulation of ataxin-3.

11 an important regulatory role for the protein ataxin-3.

12 between the ubiquitin-proteasome pathway and ataxin-3.

13 in-3 being as efficiently degraded as normal ataxin-3.

14 ransfected cells and requires intact UIMs in ataxin-3.

15 rils similar to those described for expanded ataxin-3.

16 CAG repeat in the gene encoding the protein ataxin-3.

17 yQ-containing, carboxyl-terminal fragment of ataxin-3.

18 ar inclusions containing the mutant protein, ataxin-3.

19 gregation of truncated or full-length mutant ataxin-3.

20 against the recombinant gene product, called ataxin-3.

21 rupting this interaction decreases levels of ataxin-3.

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

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

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

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

26 -3-84Q zebrafish swim shorter distances than ataxin-3-23Q zebrafish as early as 6 days old, even if e

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

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

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

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

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

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

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

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

35 Normal human ataxin-3--a polyubiquitin binding protein with ubiquitin

36 (SCA3/MJD), we show that the disease protein ataxin-3 accumulates in ubiquitinated intranuclear inclu

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

38 disease and a potential therapeutic role of ataxin-3 activity for polyglutamine disorders.

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

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

41 Q78 ataxin-3 aggregates strongly and could be purified only

42 s commonly, Hsp70 chaperones to intranuclear ataxin-3 aggregates.

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

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

45 Enzymatically active ataxin-3 also showed a greater tendency to concentrate i

46 sed that a toxic cleavage fragment of mutant ataxin-3 alternatively spliced isoform mjd1a triggers ne

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

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

49 ologic ataxin-3 fragment, full-length mutant ataxin-3 and an unrelated GFP-polyglutamine fusion prote

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

51 at this reflects direct interactions between ataxin-3 and higher order ubiquitin conjugates; ataxin-3

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

53 either of two mutant polyglutamine proteins, ataxin-3 and huntingtin, support a model of disease in w

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

55 enhances the stability of a complex between ataxin-3 and polyubiquitinated proteins.

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

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

58 ne products (huntingtin, atrophin-1 (DRPLA), ataxin-3, and androgen receptor) associated with these o

59 tates for an expanded polyglutamine protein, ataxin-3, and establish that nuclear inclusions formed b

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

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

62 y and aggregation properties of non-expanded ataxin-3 are determined by those of the Josephin domain,

63 haviours of the isolated Josephin domain and ataxin-3 are extremely similar.

64 The function of ataxin-3 as a de-ubiquitinating enzyme, its post-transla

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

66 Our results establish ataxin-3 as a poly-ubiquitin-binding protein, thereby li

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

68 protein interactions normally undertaken by ataxin-3, as both normal and mutant full-length ataxin-3

69 Additionally, ataxin-3 associates with the ubiquitin- and proteasome-b

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

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

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

73 utamine-containing neurodegenerative protein ataxin 3 (AT3) has deubiquitylating activity and binds u

74 Expansion of a polyglutamine tract in ataxin-3 (AT3) results in spinocerebellar ataxia type 3/

75 glutamine neurodegenerative disease protein, ataxin-3 (AT3), functions in the ubiquitin-proteasome pa

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

77 Here we report the finding of ataxin-3 (Atx-3), whose mutation is implicated in the ne

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

79 ation of misfolded ER proteins also involves ataxin-3 (atx3), a p97-associated deubiquitinating enzym

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

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

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

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

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

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

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

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

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

89 is degraded by the proteasome, with expanded ataxin-3 being as efficiently degraded as normal ataxin-

90 nteraction motifs (UIMs), normal or expanded ataxin-3 binds a broad range of ubiquitinated proteins t

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

92 xin-3 and higher order ubiquitin conjugates; ataxin-3 binds K48-linked tetraubiquitin but not di-ubiq

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

94 ected neural cell lines, normal and expanded ataxin-3 both co-precipitate with poly-ubiquitinated pro

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

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

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

98 e further show that both normal and expanded ataxin-3 can undergo oligoubiquitination.

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

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

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

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

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

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

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

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

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

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

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

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

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

112 xin-3, as both normal and mutant full-length ataxin-3 co-immunoprecipitate with CBP and sediment on d

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

114 but we find that it also binds a fragment of ataxin-3 containing a normal glutamine repeat.

115 The protein ataxin-3 contains a polyglutamine region; increasing the

116 Slower degradation of inactive ataxin-3 correlated with reduced interaction with the pr

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

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

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

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

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

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

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

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

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

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

127 onance binding analyses, normal and expanded ataxin-3 display similar submicromolar dissociation cons

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

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

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

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

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

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

134 erefore sought to determine the influence of ataxin-3 enzymatic activity on various cellular properti

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

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

137 Finally, we show that mutant ataxin-3 forms insoluble intranuclear complexes, or micr

138 uclear localization promotes aggregation: an ataxin-3 fragment containing a nonpathologic repeat of 2

139 oplasm into NI seeded either by a pathologic ataxin-3 fragment or by a second unrelated glutamine-rep

140 ration of transgenic rats expressing a human ataxin-3 fragment with an elongated polyglutamyl stretch

141 xpanded polyglutamine proteins: a pathologic ataxin-3 fragment, full-length mutant ataxin-3 and an un

142 nd cytotoxicity of an expanded polyglutamine ataxin-3 fragment.

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

144 -3 isoforms affect not only major aspects of ataxin-3 function but also MJD pathogenesis.

145 ed oligoubiquitination of ataxin-3 modulates ataxin-3 function rather than stability.

146 We propose that ataxin-3 functions as a polyubiquitin chain-editing enzy

147 biquitin-binding domains, which suggest that ataxin-3 functions in ubiquitin-dependent protein survei

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

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

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

151 The polyQ disease protein, ataxin-3, has predicted ubiquitin-specific protease and

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

153 The restricted expression of ataxin-3 in certain regions, however, may influence the

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

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

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

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

158 axin-3 were much higher than those of active ataxin-3, in part reflecting slower degradation.

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

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

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

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

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

164 -terminal polyglutamine-containing domain of ataxin-3 inhibits coactivator-dependent transcription an

165 The N-terminal domain of ataxin-3 inhibits histone acetylation by p300 in vitro a

166 tion, indicating a functional consequence of ataxin-3 interactions with CBP.

167 Ataxin-3 interacts with the proteasome-associated protei

168 We report that ataxin-3 interacts with ubiquitinated proteins, can bind

169 show that the polyglutamine disease protein, ataxin-3, interacts with the major histone acetyltransfe

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

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

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

173 ), findings that support the hypothesis that ataxin-3 is a proteasome-associated factor that mediates

174 polyglutamine (polyQ) region in the protein ataxin-3 is associated with spinocerebellar ataxia type

175 This conformationally altered ataxin-3 is bound to the nuclear matrix.

176 Importantly, endogenous ataxin-3 is co-immunoprecipitated with each of these coa

177 Finally, pulse-chase labeling reveals that ataxin-3 is degraded by the proteasome, with expanded at

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

179 Our data show that intact ataxin-3 is fully competent to form aggregates, and post

180 nism in which the thermodynamic stability of ataxin-3 is governed by the properties of the Josephin d

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

182 UIMs when the catalytic cysteine residue of ataxin-3 is mutated, suggesting that ataxin-3 ubiquitina

183 that this novel conformation of intranuclear ataxin-3 is not due to proteolysis, suggesting instead t

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

185 ain, and in transfected cells, indicate that ataxin-3 is predominantly a cytoplasmic protein that loc

186 We demonstrate that full-length ataxin-3 is readily recruited from the cytoplasm into NI

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

188 lish that the polyglutamine disease protein, ataxin-3, is a poly-ubiquitin-binding protein.

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

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

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

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

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

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

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

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

197 n of MCH neurons were generated using toxin (ataxin-3)-mediated ablation strategy.

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

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

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

201 NA-expressing neurons in the LHA, but orexin/ataxin-3 mice with a selective loss of the orexin neuron

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

203 Q71 transgenic mice expressing mutant ataxin-3 mjd1a above a critical level developed a phenot

204 A similar portion of mutant ataxin-3 mjd1a expressed in transfected neuroblastoma ce

205 transgenic mice contained an abundant mutant ataxin-3 mjd1a putative-cleavage fragment (Fragment), wh

206 we have developed a murine model for mutant ataxin-3 mjd1a toxicity and identified a putative-cleava

207 xpressing human mutant (Q71) or normal (Q20) ataxin-3 mjd1a under the control of the mouse prion prom

208 ing that UIM-mediated oligoubiquitination of ataxin-3 modulates ataxin-3 function rather than stabili

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

210 5 mice with citalopram significantly reduced ataxin 3 neuronal inclusions and astrogliosis, rescued d

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

212 1 and SER-4 were strong genetic modifiers of ataxin 3 neurotoxicity and necessary for therapeutic eff

213 The expression of a catalytically inactive ataxin-3 (normal or expanded) causes ubiquitinated prote

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

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

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

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

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

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

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

221 n disease tissue, both the normal and mutant ataxin-3 protein are expressed throughout the body and i

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

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

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

225 6 days old, even if expression of the human ataxin-3 protein is limited to motor neurons.

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

227 ated the relationship between the pathogenic ataxin-3 protein of the human disease spinocerebellar at

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

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

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

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

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

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

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

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

236 Here, we show that ataxin 1 and ataxin 3 proteins are recruited into aggregates in NIID

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

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

239 of the human prepro-orexin promoter (orexin/ataxin-3 rats).

240 sent evidence that the catalytic activity of ataxin-3 regulates its cellular turnover, ubiquitination

241 Moreover, normal ataxin-3 represses cAMP response element-binding protein

242 nclusion formation by the full-length mutant ataxin-3 required nuclear localization of the protein an

243 s and comigration with truncations of mutant ataxin-3 revealed that it contained residues C terminal

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

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

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

247 Ataxin-3 shows even greater activity toward mixed linkag

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

249 dy, we determined the domain architecture of ataxin-3, suggesting that it comprises a globular domain

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

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

252 l mechanism of transcriptional regulation by ataxin-3 that involves targeting histones, coactivators,

253 fluenced by the surrounding protein context; ataxin-3 that lacks the highly conserved, amino-terminal

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

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

256 Here we demonstrate that ataxin-3, the disease protein in SCA3/MJD, adopts a uniq

257 ranuclear aggregates formed by either mutant ataxin-3, the disease protein in spinocerebellar ataxia

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

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

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

261 Ataxin-3, the protein responsible for Spinocerebellar at

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

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

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

265 ression of a neurotoxic CAG expanded form of ataxin-3 to AgRP-expressing neurons in the arcuate.

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

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

268 from the normal length of 27 glutamines (Q27 ataxin-3) to a pathogenic length of 78 glutamines (Q78 a

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

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

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

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

273 These findings indicate that the orexin/ataxin-3 transgenic rat could provide a useful model of

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

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

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

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

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

279 idue of ataxin-3 is mutated, suggesting that ataxin-3 ubiquitination is itself regulated in trans by

280 We investigated if ataxin-3 was a proteasome-associated factor that recogni

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

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

283 inocerebellar ataxia type-3 disease protein, ataxin-3, we address two issues central to aggregation:

284 pinocerebellar ataxia type 3 disease protein ataxin-3, we demonstrate that the protein sequence surro

285 By using full-length human ataxin-3, we have investigated the changes in secondary

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

287 lar protein levels of catalytically inactive ataxin-3 were much higher than those of active ataxin-3,

288 colocalize only to NI formed by full-length ataxin-3, whereas the splicing factor SC35 colocalizes o

289 otein(s) alters the structure of full-length ataxin-3 which exposes the polyglutamine domain.

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

291 The affected protein, ataxin-3, which contains an N-terminal Josephin domain f

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

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

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

295 herited neurodegenerative disorder caused by ataxin-3 with a polyglutamine expansion.

296 The pathological form of ataxin-3 with an expanded polyglutamine domain also asso

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

298 In addition, expression of ataxin-3 within the nucleus exposes the glutamine domain

299 f SCA3/MJD may be an altered conformation of ataxin-3 within the nucleus that exposes the polyglutami

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