ライフサイエンスコーパス: SCA1

1 SCA1 belongs to a growing group of neurodegenerative dis

2 SCA1 disease may be reversible by RNAi therapy, and the

3 SCA1 displays higher activity than SCA3 in the in vitro

4 SCA1 has the intriguing feature that the disease-causing

5 SCA1 is caused by the toxic effects triggered by an expa

6 SCA1 is identical to SRB9, a suppressor of a cold-sensit

7 SCA1 pathogenesis studies support a model in which the e

8 SCA1 patients lose motor coordination and develop slurre

9 SCA1(+)NGFR(+) fractions were enriched for tumor-propaga

10 so protect against spinocerebellar ataxia 1 (SCA1)-induced neurodegeneration, suggesting a general ne

11 n a mouse model of spinocerebellar ataxia 1 (SCA1).

12 which include spinocerebellar ataxia type 1 (SCA1) and Huntington disease, are progressive, untreatab

13 Spinocerebellar Ataxia type 1 (SCA1) and Huntington's disease (HD) are two polyglutamin

14 repeat causes spinocerebellar ataxia type 1 (SCA1) and several other neurodegenerative diseases.

15 physiology of spinocerebellar ataxia type 1 (SCA1) and to evaluate repeat length instability in the c

16 carrying the spinocerebellar ataxia type 1 (SCA1) gene is modulated by subcellular distribution of a

17 carrying the spinocerebellar ataxia type 1 (SCA1) gene, a polyglutamine neurodegenerative disorder,

18 d form causes spinocerebellar ataxia type 1 (SCA1) in humans and exerts cytotoxicity in Drosophila an

19 ative disease spinocerebellar ataxia type 1 (SCA1) in the mouse, we targeted 154 CAG repeats into the

20 Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative diseas

21 Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative diseas

22 Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited progressive neurological

23 Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by exp

24 Spinocerebellar ataxia type 1 (SCA1) is a lethal neurodegenerative disorder caused by e

25 Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by an expand

26 Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expan

27 Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expan

28 Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expre

29 Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder characterized by a

30 Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative proteinopathy,

31 ative disease Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine expansion disorder characterize

32 Spinocerebellar ataxia type 1 (SCA1) is a relatively rare autosomal-dominant neurologic

33 Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, dominantly inherited neurodegen

34 Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease

35 Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorde

36 Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorde

37 Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorde

38 Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorde

39 Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorde

40 Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurological disorder cau

41 Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, polyglutamine-induced ne

42 Spinocerebellar ataxia type 1 (SCA1) is an incurable neurodegenerative disease caused b

43 Spinocerebellar ataxia type 1 (SCA1) is one of nine dominantly inherited neurodegenerat

44 Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited neurodegenerative disease

45 Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited, typically adult onset, p

46 Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative diseases cause

47 Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative disorders caus

48 Spinocerebellar ataxia type 1 (SCA1) is one of several neurological disorders caused by

49 Spinocerebellar ataxia type 1 (SCA1) is one such disease, characterized by loss of moto

50 Spinocerebellar ataxia type 1 (SCA1) is one such disease-caused by expansion of a polyg

51 ng pathogenic spinocerebellar ataxia type 1 (SCA1) or type 3 (SCA3) proteins in Drosophila larval den

52 n the largest spinocerebellar ataxia type 1 (SCA1) pedigree known.

53 ouse model of spinocerebellar ataxia type 1 (SCA1) suggest that neuronal dysfunction is reversible an

54 e toxicity in spinocerebellar ataxia type 1 (SCA1), a disease caused by a polyglutamine expansion in

55 c screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine

56 sociated with spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease of late onset with va

57 otein causing spinocerebellar ataxia type 1 (SCA1), aggregates in ubiquitin-positive nuclear inclusio

58 disease (HD), spinocerebellar ataxia type 1 (SCA1), dentatorubral pallidoluysian atrophy (DRPLA) Mach

59 ophy (DRPLA), spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (MJD), and Friedreich atax

60 ouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated compensato

61 mine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje

62 use model for spinocerebellar ataxia type 1 (SCA1), which carries an expanded CAG repeat tract at the

63 ouse model of spinocerebellar ataxia type 1 (SCA1).

64 mine disease, spinocerebellar ataxia type 1 (SCA1).

65 axin-1 causes spinocerebellar ataxia type 1 (SCA1).

66 odegenerative spinocerebellar ataxia type 1 (SCA1).

67 ouse model of spinocerebellar ataxia type 1 (SCA1; B05 mice).

68 nson disease, spinocerebellar ataxia type 1 (SCA1; ref.

69 ansion causes spinocerebellar ataxia type-1 (SCA1) and triggers the formation of nuclear inclusions (

70 t form causes spinocerebellar ataxia type-1 (SCA1).

71 odel of human spinocerebellar ataxia type 1, SCA1, where mice exhibit only moderate motor impairment,

72 icular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with

73 Each of the studied 78 SCA1 patients carried an expanded allele containing a st

74 at alter proteasome distribution in affected SCA1 patient neurons.

75 co-localize in NIs both in cell culture and SCA1 postmortem neurons.

76 tive disorders such as Parkinson disease and SCA1 in humans and GAD in mice, neither ubiquitin-positi

77 um1 caused progressive motor dysfunction and SCA1-like neurodegeneration with motor impairment, prima

78 Experiments in HD and SCA1 transgenic mice suggest a correlation between pheno

79 including KIT(+), PDGFRalpha(+), ISL1(+)and SCA1(+)cells, side population cells, cardiospheres and e

80 ubset of polyQ disorders, including SCA3 and SCA1.

81 units, vinculin, and spinocerebellar ataxia [SCA1]), growth factors (insulin-like growth factor bindi

82 of the most common spinocerebellar ataxias: SCA1, SCA2, SCA3, and SCA6.

83 retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respect

84 e, and a lethal CTD truncation mutation, but SCA1 deletion does not suppress alanine or glutamate sub

85 e surface phenotype of EpCAM+CD24+CD44+CD133-SCA1- and is closer in its properties to stem-like cells

86 In this study, we developed a conditional SCA1 mouse model to examine whether stopping expression

87 phenotype in a mammalian model, we crossbred SCA1 mice with mice over-expressing a molecular chaperon

88 nmt1(+/-) SCA1 mice, unlike their Dnmt1(+/+) SCA1 counterparts, closely reproduced the intergeneratio

89 Importantly, Dnmt1(+/-) SCA1 mice, unlike their Dnmt1(+/+) SCA1 counterparts, cl

90 ption is the cerebellum, which in HD, DRPLA, SCA1 and MJD has a smaller repeat relative to the other

91 human spino-cerebellar ataxia type 1 (early SCA1, 12 weeks) we find prolonged parallel fiber mGluR1-

92 also present transmission stability data for SCA1 and FRAXA alleles spanning the thresholds and compa

93 olecular mechanisms have been implicated for SCA1, 2, 3, 7, 13, 14, 19, 22, 27 and 28, highlighting a

94 data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other

95 lar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3.

96 diseases, we have created a model system for SCA1 by expressing the full-length human SCA1 gene in Dr

97 and women with positive genetic testing for SCA1, SCA2, SCA3, or SCA6 and with progressive, otherwis

98 eads toward the development of a therapy for SCA1.

99 a in serial size exclusion column fractions (SCA1, 9370 Da; SCA2, 9384 Da; SCA3, 9484 Da).

100 In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing

101 of this lethal phenotype and cloned a gene, SCA1 (suppressor of CTD alanine), which complements rece

102 leading to the identification of two genes (SCA1/2) mediating scAra capping.

103 After halting SCA1 expression at later stages of disease, only a parti

104 ional instability patterns observed in human SCA1 patients.

105 for SCA1 by expressing the full-length human SCA1 gene in Drosophila.

106 neurological phenotype reminiscent of human SCA1.

107 e neurological disorder that resembles human SCA1, featuring motor incoordination, cognitive deficits

108 lar ataxia (SCA) genes have been identified: SCA1, SCA2, SCA3, SCA6, and SCA7.

109 To examine whether development impacts SCA1, we used a conditional transgenic mouse model of SC

110 In SCA1 and several other polyglutamine diseases, the expan

111 In SCA1 mice, there was a depletion of RORalpha and a reduc

112 In SCA1, phosphorylation of ATXN1 at Ser-776 modulates dise

113 In SCA1, phosphorylation of ATXN1 at Ser776 is thought to b

114 In SCA1, the expanded polyglutamine tract is in the ataxin-

115 In SCA1, this expansion produces an abnormally long polyglu

116 02] per additional repeat unit; p=0.0128) in SCA1, short duration of follow-up (p<0.0001), lower age

117 he Arg(26) in SCA3, replacing the Gly(26) in SCA1, is predicted to cause structural changes that resu

118 he Ala(71) in SCA3, replacing the Gly(71) in SCA1, has no predictable effect on structure.

119 e aged; Purkinje cells, the most affected in SCA1, did not form aggregates of mutant protein until an

120 le and decrease on female transmission as in SCA1.

121 The larger size of the hydrophobic cavity in SCA1 correlates with its higher adhesion activity.

122 to some improvement in motor coordination in SCA1 mice and to a modest increase in their life span.

123 ch might contribute to the motor deficits in SCA1, and provides new insights into the mechanisms by w

124 ells may contribute to their degeneration in SCA1 animals.

125 the selective Purkinje cell degeneration in SCA1.

126 urochemicals were significantly different in SCA1[82Q] mice at 6 weeks, before major pathological and

127 um homeostasis sequentially downregulated in SCA1 mice.

128 a, are a part of the neuronal dysfunction in SCA1 transgenic mice.

129 diated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and par

130 determine the pattern of gene expression in SCA1 transgenic mice at two specific times in the diseas

131 To elucidate cellular pathways involved in SCA1, we used DNA microarrays to determine the pattern o

132 ligomer propagation is regionally limited in SCA1 and that immunotherapy targeting extracellular olig

133 e widely expressed, the neurodegeneration in SCA1 and other polyglutamine diseases selectively involv

134 tomatic and progressive neurodegeneration in SCA1 can be noninvasively monitored using MRS.

135 Similar downregulation occurred in SCA1 human tissues.

136 A prominent site of pathology in SCA1 is cerebellar Purkinje neurons where mutant ATXN1 m

137 inje cells, the primary site of pathology in SCA1.

138 havioral and neuropathological phenotypes in SCA1 knock-in mice.

139 ber of non-ataxia signs reached a plateau in SCA1, SCA2, and SCA3.

140 SCA1, and tested the role of this protein in SCA1 pathology.

141 ata define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular

142 s indicate RORalpha and Tip60 have a role in SCA1 and suggest a mechanism by which compromising cereb

143 S776 of ataxin-1 also has a critical role in SCA1 pathogenesis.

144 Inhibition of HDAC3 may yet have a role in SCA1 therapy, but our study provides cautionary evidence

145 rization of these pathways and their role in SCA1 will guide research over the next several years.

146 n of the orphan nuclear receptor RORalpha in SCA1 pathogenesis.

147 ology that are very similar to those seen in SCA1 patients.

148 sponsible for the nuclear aggregates seen in SCA1, and that overexpression of a DnaJ chaperone promot

149 le some modifier genes function similarly in SCA1 and HD Drosophila models, others have model-specifi

150 These results suggest that in SCA1 there is no clear causal relationship between the d

151 cumulates in neurons and exerts toxicity; in SCA1, this process causes progressive deterioration of m

152 n two brain regions especially vulnerable in SCA1: Although diminishing levels of both WT and mutant

153 ic sequences containing pure and interrupted SCA1 and FRAXA repeats having lengths above and below th

154 rotoxicity of ataxin-1 provides insight into SCA1 pathogenesis and identifies potential targets for t

155 To investigate SCA1 pathogenesis and to gain insight into the function

156 NT5E(+) (CD73)(+) ENG(-) (CD105)(-) LY6A(+) (SCA1)(+) BMSC subpopulation.

157 Interestingly, loss of Gfi-1 mimics SCA1 phenotypes in Purkinje cells.

158 hether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca1(154Q/+) mice to mice lac

159 logic infusion of recombinant VEGF mitigates SCA1 pathogenesis, suggesting a new therapeutic strategy

160 resent new therapeutic targets in mitigating SCA1.

161 Surprisingly, certain modifier genes modify SCA1 and HD models in opposite directions, i.e. they beh

162 enetic screens to identify genes that modify SCA1-induced neurodegeneration.

163 es the phenotype of the SCA1 knock-in mouse (SCA1(154Q/2Q)), the most physiologically relevant model

164 ataxia caused by the expression of a mutant SCA1 allele is not the result of cell death per se, but

165 and neuropathological course seen in mutant SCA1 transgenic mice.

166 Thus, expression of the mutant SCA1 allele within cerebellar Purkinje cells has diverge

167 In contrast, these mutant SCA1 mice have an increased initial exploratory behavior

168 A I patients with the three known mutations (SCA1, -2 or -3) highlights significant differences betwe

169 The ability of SCA1 and SRB mutant alleles to suppress CTD truncation m

170 therefore propose that a critical aspect of SCA1 pathogenesis involves the disruption of a nuclear m

171 n and loss of dendrites in Purkinje cells of SCA1 mice and indicate that altered somatodendritic memb

172 tic ataxin-1 inclusions in Purkinje cells of SCA1 mice.

173 After cessation of SCA1[82Q] transgene expression, mutant ataxin-1, includi

174 g a single allele of HDAC3 in the context of SCA1 was insufficient to improve cerebellar and cognitiv

175 A partial deletion of SCA1 (sca1 delta ::hisG) suppresses alanine or glutamate

176 and protein clearance in the development of SCA1.

177 s, we demonstrated that long-term feeding of SCA1-58Q mice with dantrolene alleviated age-dependent m

178 a mild exercise regimen in a mouse model of SCA1 and found a considerable improvement in survival ac

179 rexpression of CHIP in a Drosophila model of SCA1 decreases the protein steady-state levels of both e

180 Using a knock-in mouse model of SCA1 that recapitulates the selective neurodegeneration

181 used a conditional transgenic mouse model of SCA1 to delay the postnatal expression of mutant ATXN1 u

182 hosphorylation, and in a Drosophila model of SCA1, both 14-3-3 and Akt modulate neurodegeneration.

183 aused by mutant ataxin-1 in a mouse model of SCA1.

184 , the most physiologically relevant model of SCA1.

185 mine-expanded ATXN1 in a Drosophila model of SCA1.

186 auge disease progression in a mouse model of SCA1.

187 In inducible mouse models of SCA1 and Huntington disease, repression of mutant allele

188 genic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protei

189 In affected neurons of SCA1 patients and transgenic mice, mutant ataxin-1 accum

190 gle nuclear structure in affected neurons of SCA1 patients.

191 vidence that the selective neuropathology of SCA1 arises from modulation of a core functional activit

192 s Boat) locus, a highly conserved paralog of SCA1, and tested the role of this protein in SCA1 pathol

193 c insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.

194 To understand the pathogenesis of SCA1, we examined the subcellular localization of wild-t

195 llar LANP is involved in the pathogenesis of SCA1.

196 rize the developmental expression pattern of SCA1 and to identify putative functional domains in atax

197 stores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels,

198 These results show that the progression of SCA1 pathogenesis is dependent on the continuous express

199 tions within the (CAG)n or (CGG)n repeats of SCA1 or FRAXA, respectively, confer increased genetic st

200 The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery

201 esent in Purkinje cells, the primary site of SCA1 cerebellar pathology.

202 ndant in Purkinje cells, the primary site of SCA1 pathogenesis; moreover, their downregulation was me

203 ed in Purkinje cells, the primary targets of SCA1.

204 ell pathology is markedly worse than that of SCA1 mice.

205 urodegenerative diseases, as the toxicity of SCA1 and tau was also suppressed when PICK1 was down-reg

206 Importantly, the effect of NLK on SCA1 pathology is dependent upon NLK's enzymatic activit

207 kinje cell pathology similar to the original SCA1 mice.

208 molecular dynamics simulation, but overall, SCA1 displays a larger cavity than SCA3.

209 n of lineage(neg/low), CD45(pos) EpCAM(pos), SCA1(pos), CD117(neg), CD138(neg), MHCII(neg) cells as F

210 Six SCAs, including the more prevalent SCA1, SCA2, SCA3, and SCA6 along with SCA7 and SCA17 are

211 of expanded polyglutamine (poly-Q) proteins SCA1, SCA3, and huntingtin.

212 Six genes (RGS4, SCA1, GRM4, DPYSL2, NOS1, and GRID1) met this criterion

213 These findings demonstrate that SCA1 is not caused by loss of function of ataxin-1 and p

214 We found that SCA1 phenotypes could be reversed by partial suppression

215 into the function of ATXN1 and suggest that SCA1 neuropathology depends on native, not novel, protei

216 t overexpress the normal human ataxin-1 (the SCA1[30Q] line) and wild-type controls.

217 t overexpress the mutant human ataxin-1 (the SCA1[82Q] line) were measured longitudinally up to 1 yea

218 In this study we used ataxin-1, the SCA1 gene product, as a bait in the yeast two-hybrid sys

219 protein (LANP) interacts with ataxin-1, the SCA1 gene product.

220 e human ataxin-1 (the protein encoded by the SCA1 gene) and mutant ataxin-1 in the Purkinje cells of

221 Multiple neurochemicals distinguished the SCA1[82Q] mice from controls with no overlap at all ages

222 IID in the absence of a CAG expansion in the SCA1 and SCA3 genes.

223 paring the pattern of gene expression in the SCA1 ataxic B05-ataxin-1[82Q] transgenic mouse line with

224 tor cDNA, (CAG) in the HD cDNA, (CAG) in the SCA1 cDNA, (CAG) in the SCA3 cDNA and as an isolated (CA

225 tion induces a toxic gain of function in the SCA1 encoded protein ATXN1.

226 the expansion of a CAG triplet repeat in the SCA1 gene.

227 Two prominent aspects of pathology in the SCA1 mice are the presence of cytoplasmic vacuoles and d

228 nction and Purkinje neuron morphology in the SCA1 mice.

229 and to gain insight into the function of the SCA1 gene product ataxin-1, a novel protein without homo

230 et expansion within the coding region of the SCA1 gene.

231 epleting HDAC3 improves the phenotype of the SCA1 knock-in mouse (SCA1(154Q/2Q)), the most physiologi

232 identified which are able to impinge on the SCA1 disease process.

233 The findings in this family suggest that the SCA1 gene mutation can result in a disorder similar to m

234 ocerebellar ataxia genetically linked to the SCA1 locus on chromosome 6p has been screened for the CA

235 We describe 4 members of a family with the SCA1 mutation and a dominantly inherited progressive ata

236 xpansion of a polyglutamine tract within the SCA1 gene product, ataxin-1.

237 xpansion of a polyglutamine tract within the SCA1 product, ataxin-1.

238 e expansion of a glutamine repeat within the SCA1-encoded protein ataxin-1.

239 aking advantage of the availability of three SCA1 transgenic mouse lines, each expressing a different

240 Offspring of Capicua mutant mice bred to SCA1 mice showed significant improvement of all disease

241 gions, adding another level of complexity to SCA1 pathogenesis.

242 adation of mutant ataxin-1 may contribute to SCA1 pathogenesis.

243 in complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mecha

244 ontaining ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism.

245 Breeding Pum1(+/-) mice to SCA1 mice (Atxn1(154Q/+)) exacerbated disease progressio

246 agate locally in vivo in mice predisposed to SCA1 following intracerebral oligomeric tissue inoculati

247 Together, SCA1, SCA2, and SCA3/MJD constitute >40% of the mutation

248 Correspondingly, in transgenic SCA1 mouse, Boat expression is greatly reduced in Purkin

249 Spinocerebellar ataxia type1 (SCA1) is one of several neurodegenerative disorders caus

250 patients, accounting for 40%, compared with SCA1 and SCA3 which account for 35% and 15%, respectivel

251 etermine the frequency of SCA2 compared with SCA1, SCA3/Machado-Joseph disease (MJD), and dentatorubr

252 amino acid variations in SCA3, compared with SCA1.

253 A2 had higher CCFS scores than patients with SCA1 and SCA3, but similar SARA scores.

254 increase was 2.11 (SE 0.12) in patients with SCA1, 1.49 (0.07) in patients with SCA2, 1.56 (0.08) in

255 orrelate with ataxia scores of patients with SCA1, indicating their potential as reliable biomarkers

256 early, but more slowly than in patients with SCA1, SCA2, and SCA3 (p<0.0001).

257 1, 2005, and Aug 31, 2006, 526 patients with SCA1, SCA2, SCA3, or SCA6 were enrolled.