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 gene mutations are the greatest cause of Parkinson d

5 GBA gene sequencing revealed homozygosity for a novel mu

6 GBA homozygotes/compound heterozygotes had lower enzymat

7 GBA motif-containing proteins were originally reported t

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

14 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild-p.N370S and 56 severe mainly p.L44

15 tudy enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers.

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

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

18 thy controls vs 8.4 [7.3] LRRK2 vs 9.5 [9.2] GBA, p<0.0001 for both comparisons) and the Scale for Ou

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

20 maging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit.

21 dred and four idiopathic PD, 40 LRRK2-PD, 70 GBA-PD, 196 healthy non-carriers, 55 LRRK2-NMC and 97 GB

22 96 healthy non-carriers, 55 LRRK2-NMC and 97 GBA-NMC participated in this study.

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

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

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

26 es, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S).

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

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

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

30 ia a novel G-protein binding and activating (GBA) motif.

31 at contain a Galpha-binding and -activating (GBA) motif and whose dysregulation underlies human disea

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

33 mediated by a Galpha-binding-and-activating (GBA) motif that was acquired by DAPLE in vertebrates dur

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

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

36 Additionally, GBA may represent attentional effects.

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

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

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

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

41 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compoun

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

43 26K carriers (10 of 21 [47.6%]; P = .01) and GBA variant carriers (15 of 39 [38.5%]; P = .04) progres

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

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

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

47 genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons wer

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

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

50 set of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 parti

51 hether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's dis

52 mpared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased

53 se impairment) on the phenotype of LRRK2 and GBA Parkinson's disease (PD), and on the prevalence of p

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

55 number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spe

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

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

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

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

60 sts, specific PD gene target agents (such as GBA or LRRK2 modifiers) and other potential disease modi

61 an association between DLB and genes such as GBA.

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

63 Variants in the ASH1L/GBA (Chr1q22) and APOE epsilon4 (Chr19) loci were associ

64 clude homology search, guilt-by-association (GBA), and CRISPR-Cas self-targeting spacers.

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

66 erated by treatment with the mechanism-based GBA inhibitors, conduritol B epoxide (CBE), and cyclophe

67 datasets); (iii) it combines homology-based, GBA-based, and self-targeting approaches in one software

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

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

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

71 ggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-de

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

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

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

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

76 associated regulator) database (populated by GBA-based Acr and Aca datasets); (iii) it combines homol

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

78 Five genes (CNN2, GBA, GSTP1, MINT2 and FERMT2) in neurons and nine genes

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

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

81 After confirming GBA knockout of HEK 293 and A549 cells by both Western b

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

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

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

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

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

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

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

89 Finally, GBA but not LRRK2 non-manifesting carriers showed increa

90 e virus studies suggested a general role for GBA along the endocytic pathway, we tested that hypothes

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

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

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

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

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

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

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

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

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

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

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

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

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

104 ut mutations on the glucocerebrosidase gene (GBA).

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

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

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

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

109 he lysosomal enzyme beta-glucocerebrosidase (GBA).

110 ns to the lysosomal beta-glucocerebrosidase (GBA).

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

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

113 inherited deficiency in glucocerebrosidase (GBA, a retaining beta-glucosidase), and deficiency in GB

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

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

116 oids via an inhibitor of glucocerebrosidase (GBA, the enzyme that degrades glucosylceramide), colonoi

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

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

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

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

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

122 its metabolizing enzyme glucosylceramidase (GBA).

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

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

125 = 14, 52.6 +/- 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson

126 ompared with baseline in both the GD and Het GBA groups.

127 e 1 (GD), 29 GBA1 heterozygous carriers (Het GBA group) and 30 controls (HC) at baseline and followed

128 In GBA1 mutation-positive individuals (Het GBA and GD), an UPSIT score of 23 at baseline was correl

129 S, MoCA and MDS-UPDRS III than HC, while Het GBA displayed worse outcomes in UPSIT and MDS-UPDRS III

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

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

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

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

134 By fusing human GBA to an exosome-anchoring protein: vesicular stomatiti

135 ed virus (AAV) serotype 9 carrying the human GBA gene under control of a neuron-specific promoter to

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

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

138 taining beta-glucosidase), and deficiency in GBA constitutes the largest known genetic risk factor fo

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

140 .2, P = 0.003) were significantly greater in GBA mutation carriers.

141 degradation of its receptor were impaired in GBA knockout cells.

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

143 artments exhibited a significant increase in GBA activity.

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

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

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

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

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

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

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

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

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

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

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

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

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

157 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not wi

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

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

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

161 Variants in GBA, encoding the enzyme glucocerebrosidase, are associa

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

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

164 stomatitis virus (VSV), and measles virus in GBA knockout cells.

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

166 sease-associated genetic mutations including GBA and LRRK2 .

167 rongly support the hypothesis that increased GBA signals PEs.

168 is what other genetic factors that influence GBA-associated risk for disease, and whether these overl

169 RRK2 carriers, MS does not seem to influence GBA and LRRK2-PD phenotype.

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

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

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

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

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

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

176 Mutant GBA-induced SNCA accumulation could be pharmacologically

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

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

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

180 utations results from the presence of mutant GBA alleles.

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

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

183 delineating the mechanisms underlying mutant GBA-associated PD.

184 molecular mechanisms linking PD with mutant GBA alleles.

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

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

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

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

189 se and decreases age at onset in carriers of GBA variants.

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

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

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

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

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

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

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

197 provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset

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

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

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

201 e results have implications for selection of GBA carriers for therapeutic interventions.

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

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

204 osomal function exerts the largest effect on GBA associated risk for disease.

205 c risk score to detect genetic influences on GBA risk and age at onset.

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

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

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

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

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

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

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

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

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

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

216 gression and define the G-protein regulatory GBA motif as one of the minimal modules essential for Da

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

218 Here, we show that DAPLE's GBA motif, in addition to Galpha(i), binds efficiently t

219 c substituent at C8 are potent and selective GBA inhibitors and that an unambiguous Gaucher animal mo

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

221 the locations of the fifteenth and sixteenth GBA members were incorrectly given as '(15) Australian G

222 this effect was consistent across all tested GBA risk variants.

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

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

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

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

227 ) and Galpha(q) These findings indicate that GBA motifs have versatility in their G-protein-modulatin

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

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

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

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

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

233 Collectively, our findings suggest that GBA is critically important for endocytic trafficking of

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

235 33 patients undergoing further analysis, the GBA mutation carriers were younger at symptom onset (mea

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

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

238 f iPSC-derived dopamine neurons carrying the GBA-N370S PD risk variant, we identified a progressive a

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

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

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

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

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

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

245 aucher disease is caused by mutations in the GBA gene, which encodes for the lysosomal enzyme beta-gl

246 Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebr

247 , 11 (31%) were carriers of mutations in the GBA gene.

248 imperfect correlation with mutations in the GBA gene.

249 We pinpointed Met-1669 as the residue in the GBA motif of DAPLE that diverges from that in GIV and en

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

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

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

253 t always the case, as phosphorylation of the GBA motif of GIV promotes its binding to Galpha(s) and i

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

255 Interestingly, activity of the GBA-encoded enzyme, beta-glucocerebrosidase, was increas

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

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

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

259 ooperatively suppress tumor growth via their GBA motif, only the full-length transcript triggers EMT

260 Thus, GBA variants influence the heterogeneity in symptom prog

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

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

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

264 caudate (healthy controls 2.98 [SD 0.63] vs GBA 3.26 [0.63]; p<0.0001), putamen (2.15 [0.56] vs 2.48

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

266 However, when GBA was inhibited, TJP1 levels remained stable, suggesti

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

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

269 To examine whether GBA is required for other enveloped viruses, we compared

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

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

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

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

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

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

276 increased cognitive decline associated with GBA-PD.

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

278 acteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls.

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

280 y to produce engineered exosomes loaded with GBA in two different spatial configurations for targeted

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

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

283 Patients with GBA-associated parkinsonism exhibit varying parkinsonian

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

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

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

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

288 ogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%).

289 We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands

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

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

292 significantly between cases with and without GBA sequence variants.

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

294 nges than patients with parkinsonism without GBA mutations.

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

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

297 mutations and 41 patients having PD without GBA mutations.

298 more cognitive impairment than those without GBA mutations.

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

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