ライフサイエンスコーパス: GBA

1 GBA deficiency causes the accumulation of two key sphing

2 GBA encodes for glucocerebrosidase (GCase), the enzyme d

3 GBA encodes the lysosomal enzyme glucocerebrosidase (GCa

4 GBA finds short subsequences as LCR candidates by traver

5 GBA gene mutations are the greatest cause of Parkinson d

6 GBA gene sequencing revealed homozygosity for a novel mu

7 GBA homozygotes/compound heterozygotes had lower enzymat

8 GBA mutations (beta = 4.65; 95% CI, 1.72-7.58; P = .002)

9 GBA mutations often result in protein misfolding and pre

10 GBA noncarrier non-PD spouse control participants were r

11 GBA proteins have important roles in physiology and dise

12 GBA reaches lysosomes via association with its receptor,

13 GBA reactivity was unaffected by DNase treatment of sera

14 GBA was fully sequenced for 1883 non-Ashkenazi Jewish pa

15 Glucocerebrosidase 1 (GBA) mutations responsible for Gaucher disease (GD) are

16 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild-p.N370S and 56 severe mainly p.L44

17 abundant alpha-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage

18 eps in the trafficking pathway of the LIMP-2/GBA complex.

19 ium, which was attenuated by limiting LIMP-2/GBA exit from the Golgi by PI4KIIIbeta inhibitors.

20 ochemical profiling was available for all 20 GBA-associated PD cases, as well as a subset (87 of 242)

21 s compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlie

22 nal and medicinal chemistry, we identified a GBA analog, referred to as DAP-19, which binds potently

23 Isofagomine, a GBA chaperone, showed a related trend.

24 tients diagnosed with DLB were carriers of a GBA mutation, making it the most common genetic mutation

25 o did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were mo

26 how that the natural product, gambogic acid (GBA), binds selectively to a site in the middle domain o

27 le contains a Galpha-binding and activating (GBA) motif, which activates Galphai proteins and an adja

28 nce named the Galpha-binding and activating (GBA) motif, which confers guanine nucleotide exchange fa

29 containing a Galpha-binding and -activating (GBA) motif.

30 terized by synchronized gamma-band activity (GBA) [5-11] that reflects stimulus-specific representati

31 e signaled by increased gamma-band activity (GBA) in the cortical area where prediction and evidence

32 Additionally, GBA may represent attentional effects.

33 DLB underwent genotyping for the 7 known AJ GBA mutations and the LRRK2 G2019S mutation.

34 Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 micromol/l/h, versus 12.11

35 We observed that overexpression of all GBA mutants examined (N370S, L444P, D409H, D409V, E235A,

36 ncreased GCase levels and activity, but also GBA mRNA, in control and mutant GBA fibroblasts.

37 r extension technique, Genetic Bit Analysis (GBA), we confirmed the presence of a subset of these can

38 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compoun

39 /h versus 7.88 micromol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA

40 26K carriers (10 of 21 [47.6%]; P = .01) and GBA variant carriers (15 of 39 [38.5%]; P = .04) progres

41 eta = 3.42; 95% CI, 0.66-6.17; P = .02), and GBA variants combined as a single group (beta = 4.01; 95

42 )), MAPT (OR = 0.62, P = 1.78 x 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 x

43 The association between interleukin 8 and GBA mutation status was replicated (P = .03) in a separa

44 al significance between patients with GD and GBA heterozygotes (P = .07, log-rank test).

45 Patients with GD and GBA heterozygotes have an increased age-specific risk fo

46 in-positive neuropathology (SNCA, LRRK2, and GBA) are brought together by involvement in the autophag

47 re at the last assessment as the outcome and GBA genotype as the independent variable, with adjustmen

48 Overall, 10.3% of patients with PD and GBA sequencing carried a mutation.

49 fied more than 1 risk allele within SNCA and GBA.

50 ied bone allograft (DFDBA) plus antibiotics (GBA or test group) or with a polylactide membrane and DF

51 The odds ratio for any GBA mutation in patients versus controls was 5.43 across

52 ce and organization of a 75-kb region around GBA, including the duplicated region containing GBA and

53 ich are transcribed in the same direction as GBA.

54 nes, and affect highly studied genes such as GBA and CYP2E1.

55 th or without Parkinson's disease-as well as GBA-negative patients with Parkinson's disease, compared

56 Recently a glomerular binding assay (GBA) has been developed to detect IgG binding to isolate

57 ofiling data sets, the guilt by association (GBA) principle has been a cornerstone for deriving gene

58 We use guilt-by-association (GBA) to analyze this data set and identify coexpressed g

59 y functionally linked [guilt-by-association (GBA), guilt-by-profiling].

60 using a method we call Guilt-by-Association (GBA), on the basis of a combinatoric measure of associat

61 was used to test for an association between GBA genotype and motor progression, with the Movement Di

62 The association between GBA genotype and progression status was then tested usin

63 e that there is a strong association between GBA mutations and Parkinson's disease.

64 chanisms are fundamentally different between GBA proteins and GPCRs, and that GEF-mediated perturbati

65 odels to investigate the interaction between GBA mutations and synucleinopathies.

66 anonical GPCR-G protein signaling but blocks GBA-dependent signaling in cancer cells.

67 of lower glucocerebrosidase activity in both GBA mutation carriers and Parkinson's patients without G

68 d compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis.

69 develop a novel graph-based algorithm called GBA to identify LCRs in a protein sequence.

70 ase are over five times more likely to carry GBA mutations than healthy controls.

71 Of the causative GBA mutations, N370S is particularly frequent in the AJ

72 Combined GBA variants (beta = 0.38; 95% CI, 0.23-0.53; P = .01) a

73 Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73;

74 , including the duplicated region containing GBA and MTX.

75 r genes in this region (CLK2, propin, COTE1, GBA, metaxin, and thrombospondin 3) are overexpressed in

76 ded age, sex, and assay batch as covariates, GBA mutation status was significantly associated with pl

77 Consistent with clinical data, GBA carriers showed reduced posterior parietal and occip

78 nterfere with lysosomal protein degradation, GBA heterozygotes may demonstrate reduced lysosomal SNCA

79 Fourteen different GBA mutations were identified, including three previousl

80 of efficient tools that specifically disrupt GBA motif function in the context of the large multifunc

81 were compared between cases who were either GBA mutation carriers, polymorphism carriers or wild-typ

82 esign, Setting, and Participants: The entire GBA coding region was screened for mutations and E326K i

83 At last examination, GBA carriers had worse motor symptoms, particularly nond

84 conserved haplotype at four markers flanking GBA (PKLR, D1S1595, D1S2721, and D1S2777) was observed o

85 repeat and the evolution of a pseudogene for GBA.

86 e duplication leading to the pseudogenes for GBA and MTX are now clearly established.

87 lts not only point to a fundamental role for GBA in immune regulation but also suggest that GBA mutat

88 niversity, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutatio

89 a disease-modifying therapeutic strategy for GBA-related synucleinopathies and conceivably for certai

90 In addition, increased high-frequency GBA for expected illumination was observed in brain area

91 In high-frequency GBA we also observed a late interaction effect in visual

92 ic studies reveal that mutations in the gene GBA are the most widespread genetic risk factor for park

93 Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most com

94 of mutations in the glucocerebrosidase gene (GBA) are at increased risk of developing Parkinson's dis

95 tations in the beta-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homoz

96 Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's

97 s the presence of a glucocerebrosidase gene (GBA) mutation.

98 Mutations in the glucocerebrosidase gene (GBA) represent a significant risk factor for developing

99 by mutations in the glucocerebrosidase gene (GBA), is the most common lysosomal storage disease.

100 Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk

101 ut mutations on the glucocerebrosidase gene (GBA).

102 ta-glucocerebrosidase (GCase) encoding gene, GBA, which leads to accumulation of glucosylceramides.

103 Glucocerebrosidase (GBA) mutations have been associated with Parkinson's dis

104 t kinase 2 (LRRK-2), and glucocerebrosidase (GBA) have shown that genetic predisposition is another i

105 Gaucher disease (GD) and glucocerebrosidase (GBA) heterozygotes is important for understanding the pa

106 ex, depression, and beta-glucocerebrosidase (GBA) mutation status were included in the prediction mod

107 he lysosomal enzyme beta-glucocerebrosidase (GBA).

108 in the GBA gene encoding glucocerebrosidase (GBA) are known to interfere with lysosomal protein degra

109 ons in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, am

110 in the lysosomal enzyme glucocerebrosidase (GBA) gene are at significantly high risk of developing P

111 the functional gene for glucocerebrosidase (GBA) and its pseudogene (psGBA), located in close proxim

112 iciency of the lysosomal glucocerebrosidase (GBA) due to mutations in the GBA gene results in Gaucher

113 functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramid

114 rtance: Mutations in the glucocerebrosidase (GBA) gene are a risk factor for the development of demen

115 gene, a mutation in the glucocerebrosidase (GBA) gene, or both.

116 Mutations in the glucocerebrosidase (GBA) gene, which encodes the lysosomal enzyme that is de

117 ramide-degrading enzyme (glucocerebrosidase, GBA), CBE inactivated GBA2 less efficiently, due to a lo

118 thod by using the retaining beta-glucosidase GBA (CAZy glycosylhydrolase family GH30) and then applie

119 deficient activity of acid beta-glucosidase (GBA).

120 ynthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining beta-glucosidase, GBA3

121 This study indicates that, as a group, GBA mutation-positive individuals show a deterioration i

122 = 14, 52.6 +/- 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson

123 e (GCase) in PD brains carrying heterozygote GBA mutations (PD+GBA) and sporadic PD brains.

124 ed a diagnosis of type 1 GD, 28 heterozygous GBA mutation carriers, and 26 genetically unrelated cont

125 type 1 Gaucher disease (GD) and heterozygous GBA mutation carriers were recruited in 2010 from the Ly

126 ast cells from PD patients with heterozygous GBA mutations and Drosophila expressing human wild-type,

127 d by increases in high-frequency (68-140 Hz) GBA.

128 Clinical data on all identified GBA mutation carriers was reviewed and analysed.

129 the middle domain of Hsp90beta, identifying GBA as an Hsp90beta-specific Hsp90 inhibitor.

130 the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzy

131 .2, P = 0.003) were significantly greater in GBA mutation carriers.

132 specific pattern of cognitive impairment in GBA mutation versus Parkinson's disease is potentially i

133 dies demonstrated that the D137N mutation in GBA is a pathogenic mutation, and immunohistochemistry c

134 Heterozygous mutations in GBA are a major risk factor for Parkinson's disease.

135 e and an increased frequency of mutations in GBA has been reported in several different ethnic series

136 the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression rema

137 Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme de

138 Worst recall was observed in GBA-positive cases with Parkinson's disease.

139 The deficit observed in GBA-positive individuals, regardless of whether they had

140 accumulating in GD, mediates PD pathology in GBA-associated PD.

141 also show that carriers of polymorphisms in GBA which are not generally considered to increase Parki

142 a significant deficit in memory precision in GBA-positive individuals-with or without Parkinson's dis

143 Biochemical abnormalities present in GBA (mut/wt) carriers may offer new pathogenetic insight

144 ith Parkinson's disease, are also present in GBA-positive individuals-both with and without Parkinson

145 Survival is reduced in GBA carriers compared to noncarriers; this seems to be p

146 from bone marrow may, in fact, be reduced in GBA deficiency.

147 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not wi

148 Pregnant AJ couples, carrying mutation(s) in GBA, which encodes acid beta-glucosidase, were recruited

149 previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the fin

150 The carrier frequency of genetic variants in GBA was determined.

151 r results indicate that genetic variation in GBA has an important impact on the natural history of Pa

152 ffects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated usi

153 within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a second

154 sease-associated genetic mutations including GBA and LRRK2 .

155 rongly support the hypothesis that increased GBA signals PEs.

156 y encoded protein that specifically inhibits GBA motifs: GBA inhibitor (GBAi).

157 favoring high-affinity binding to all known GBA motifs.

158 expressing human wild-type, N370S and L444P GBA with the molecular chaperones ambroxol and isofagomi

159 ild-type Gba or heterozygosity for the L444P GBA mutation associated with Gaucher disease.

160 at the acid beta-glucosidase (GCase) locus (GBA).

161 depletion also caused secretion of missorted GBA into the medium, which was attenuated by limiting LI

162 otein that specifically inhibits GBA motifs: GBA inhibitor (GBAi).

163 Mutant GBA-induced SNCA accumulation could be pharmacologically

164 rongly suggest that the presence of a mutant GBA allele in dopaminergic cells leads to ER stress and

165 ty, but also GBA mRNA, in control and mutant GBA fibroblasts.

166 ouble heterozygous for the endogenous mutant GBA orthologs presented Unfolded Protein Response (UPR)

167 utations results from the presence of mutant GBA alleles.

168 small molecule chaperones can reverse mutant GBA-mediated ER stress in vivo and might prove effective

169 tive therapeutic targets for treating mutant GBA-associated PD.

170 delineating the mechanisms underlying mutant GBA-associated PD.

171 molecular mechanisms linking PD with mutant GBA alleles.

172 Expression of mutated GBA in Drosophila resulted in dopaminergic neuronal loss

173 This paper describes the use of N-GBA arrays designed to scan the sequence of a 33 base re

174 = 427), among their parents who are obligate GBA mutation carriers (heterozygotes, n = 694), and amon

175 ressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-pene

176 o map changes in Galpha caused by binding of GBA proteins with residue-level resolution.

177 Clinical characteristics of GBA-associated PD cases were compared with those of 242

178 mportant regulators of lysosomal delivery of GBA, revealing a new element of control to sphingolipid

179 To examine the effect of GBA genotype on cognitive progression, patients were cla

180 iation signal was robust to the exclusion of GBA, and consistent results were obtained in two indepen

181 The frequency of GBA mutations among the British patients (33/790 = 4.18%

182 We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients

183 In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson'

184 The frequency of GBA mutations in unselected Parkinson's disease populati

185 body disorders had an increased frequency of GBA mutations when compared with control individuals.

186 s studies have investigated the influence of GBA mutations on the natural history of Parkinson's dise

187 provide insight into the pathophysiology of GBA-associated parkinsonism.

188 predict gene function using the principle of GBA.

189 ents with Parkinson's disease, regardless of GBA status, was explained by increased random responses.

190 Until now, the role of GBA for the formation of dynamically changing representa

191 Targeted next-generation sequencing of GBA-flanking SNPs was performed on peripheral blood samp

192 est a relationship between specific types of GBA mutations and aggressive cognitive decline and have

193 riants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogeni

194 ovarian and kidney cancers, thus proving our GBA hypothesis.

195 vity for Hsp90beta among all Hsp90 paralogs, GBA thus provides a new chemical tool to study the uniqu

196 ase in GCase activity was observed in all PD+GBA brain areas except the frontal cortex.

197 GCase protein expression was lower in PD+GBA and PD brains, whereas increased C/EBP homologous pr

198 ains carrying heterozygote GBA mutations (PD+GBA) and sporadic PD brains.

199 utamen, amygdala, and substantia nigra of PD+GBA (n = 9-14) and sporadic PD brains (n = 12-14).

200 nselected UK Parkinson's disease population, GBA mutations are present at a frequency of 3.5%.

201 of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cas

202 y occurring Gaucher mutation, L444P, reduced GBA activity by 40%, reduced SNCA degradation and trigge

203 Conclusions and Relevance: GBA variants predict a more rapid progression of cogniti

204 o located within the 16 kb of DNA separating GBA from psGBA.

205 ed the effects of wild-type (WT) and several GBA mutants on SNCA in cellular and in vivo models using

206 erozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 micromol/l/h versus 11.

207 erozygotes had lower enzymatic activity than GBA heterozygotes (0.85 micromol/l/h versus 7.88 micromo

208 ents with GD had a younger age at onset than GBA heterozygotes (mean, 54.2 vs 65.2 years, respectivel

209 Our results demonstrate that GBA mutants promote SNCA accumulation in a dose- and tim

210 This study demonstrates that GBA mutations are found in British subjects at a higher

211 We found that GBA patterns during successful (but not unsuccessful) re

212 alyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for th

213 d in further studies, this may indicate that GBA mutation status could be used as a prognostic marker

214 with Parkinson's disease and indicates that GBA mutations make an important contribution to Parkinso

215 duration of symptoms, testing revealed that GBA mutation carriers had poorer cognition as assessed b

216 Our experiments on real data show that GBA has significantly higher recall compared to existing

217 , by implementing GBAi in vivo, we show that GBA-dependent signaling modulates phenotypes during Xeno

218 However, recent studies have shown that GBA is closely correlated with the overall amount of cel

219 A in immune regulation but also suggest that GBA mutations in GD may cause widespread immune dysregul

220 33 patients undergoing further analysis, the GBA mutation carriers were younger at symptom onset (mea

221 mentia for both the patients with GD and the GBA mutation carriers and any existing neurological dise

222 ate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, an

223 e used to map a 9.3-cM region containing the GBA locus and to genotype 261 AJ N370S chromosomes, 60 E

224 to affect regenerative healing in either the GBA or GB groups.

225 etween smokers and non-smokers in either the GBA or GB groups.

226 reductions at 9 months were greater for the GBA group than for the GB group (2.92+/-1.78 versus 2.50

227 se (GCase) due to biallelic mutations in the GBA (glucosidase, beta, acid) gene causes the classic ma

228 As mutations in the GBA gene encoding glucocerebrosidase (GBA) are known to

229 Mutations in the GBA gene pathogenic for neuropathic GD and complex allel

230 ocerebrosidase (GBA) due to mutations in the GBA gene results in Gaucher disease (GD).

231 Mutations in the GBA gene that encodes glucocerebrosidase cause the lysos

232 Mutations in the GBA gene were associated with more severe motor and cogn

233 imperfect correlation with mutations in the GBA gene.

234 , 11 (31%) were carriers of mutations in the GBA gene.

235 Seven of 12 furcations (58%) in the GBA group demonstrated >50% vertical defect fill at 9 mo

236 odies that directly bind to glomeruli in the GBA.

237 type of Galpha(i)-regulatory motif named the GBA motif (for Galpha-binding and -activating motif), wh

238 n, supporting a specific contribution of the GBA gene or lysosome function to this clinical syndrome.

239 aucher disease is caused by mutations of the GBA gene that encodes the lysosomal enzyme glucocerebros

240 Sequencing of the GBA was performed after two-stage polymerase chain react

241 ases, as well as a subset (87 of 242) of the GBA-negative PD cases.

242 equence of the entire region surrounding the GBA gene.

243 We find that the GBA motif binds to the SwitchII/alpha3 cleft of Galpha a

244 We have used the GBA to study sera from four groups of SLE patients: (A)

245 immune cell aberrations in mice in which the GBA gene is deleted conditionally in hematopoietic stem

246 thnicity, to screen for mutations within the GBA gene.

247 Thus, GBA variants influence the heterogeneity in symptom prog

248 at onset, and disease duration attributed to GBA carriers a greater risk for dementia (hazard ratio [

249 f these three genes, the gene most distal to GBA is a protein kinase (clk2).

250 ne of unknown function lies most proximal to GBA.

251 nes within the 32 kb of sequence upstream to GBA, all of which are transcribed in the same direction

252 All 16 centers could detect two GBA mutations, L444P and N370S.

253 Drosophila has two GBA orthologs (CG31148 and CG31414), each of which has a

254 on of the pathological mechanisms underlying GBA-associated parkinsonism will improve our understandi

255 Using GBA, we have examined the expression of 40,000 human gen

256 Individuals who were GBA-positive and also had Parkinson's disease suffered f

257 ent with a primary pathogenic cause, whereas GBA increases risk across all forms of PD.

258 Objective: To determine whether GBA mutations and the E326K polymorphism modify PD sympt

259 We investigated whether GBA mutations alter the neurobiology of Parkinson diseas

260 with those of 242 patients having PD in whom GBA mutations were excluded by full gene sequencing.

261 SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5x10(-8) Combined Sample) (N370;

262 ion between sources of error associated with GBA mutation and Parkinson's disease.

263 of visual short-term memory associated with GBA mutation and with Parkinson's disease.

264 zymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson's

265 GCase deficiency in PD brains with GBA mutations is a combination of decreased catalytic ac

266 ess the association of phenotype of DLB with GBA mutations, and explore the effects of these mutation

267 d to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease co

268 Patients with GBA mutations generally have an earlier onset of Parkins

269 continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of

270 Patients with GBA-associated parkinsonism exhibit varying parkinsonian

271 n cohort included 19 patients having PD with GBA mutations and 41 patients having PD without GBA muta

272 Patients having PD with GBA mutations have earlier age at disease onset and are

273 thout GBA mutations, patients having PD with GBA mutations were younger at disease onset (P = .04) an

274 s may be elevated in patients having PD with GBA mutations.

275 identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk

276 517) and controls (n = 252) with and without GBA mutations.

277 significantly between cases with and without GBA sequence variants.

278 (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 +/- 7.1 years); (iii) patien

279 ared to sporadic Parkinson's disease without GBA mutations.

280 nges than patients with parkinsonism without GBA mutations.

281 on carriers and Parkinson's patients without GBA mutations suggests that loss of glucocerebrosidase f

282 Compared with patients having PD without GBA mutations, patients having PD with GBA mutations wer

283 mutations and 41 patients having PD without GBA mutations.

284 more cognitive impairment than those without GBA mutations.

285 cohort of patients having PD with vs without GBA mutations.

286 Overexpression of WT GBA in neural and HEK293-SNCA cells increased GCase acti