ライフサイエンスコーパス: LRRK2

1 sociated genetic mutations including GBA and LRRK2 .

2 au (MAPT), and leucine-rich repeat kinase 2 (LRRK2).

3 patients, operates in a common pathway with LRRK2.

4 son's disease (PD) is caused by mutations in LRRK2.

5 ary neurons and a Drosophila model of G2019S LRRK2.

6 ich is required for the synaptic function of LRRK2.

7 required direct binding of 14-3-3theta with LRRK2.

8 opein promoted the kinase activity of G2019S-LRRK2.

9 cell death, have been shown to interact with LRRK2.

10 19S) and GTPase (R1441C) encoding domains of LRRK2.

11 rization and disease-associated mutations in LRRK2.

12 te of Dictyostelium Roco4 kinase to resemble LRRK2.

13 Golgi and activated by Rab29 than wild-type LRRK2.

14 ally available, brain-penetrant inhibitor of LRRK2.

15 ancer screen to uncover genetic modifiers of LRRK2.

16 estigate the signalling events through which LRRK2 acts to influence macroautophagy, the mammalian ta

17 These findings suggest that LRRK2 affects epigenetic histone modification and neuron

18 rough K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neu

19 LRRK2 also inhibited myocyte-specific enhancer factor 2D

20 alized the metabolism and location of mutant LRRK2 and alpha-synuclein in living neurons at the singl

21 The interaction between G2019S-LRRK2 and alpha-synuclein may uncover new mechanisms and

22 Here, we show that inactivation of LRRK2 and its functional homolog LRRK1 results in earlie

23 s on the phosphoproteome: activation of both LRRK2 and PINK1 leads to phosphorylation of several memb

24 In C. elegans neurons, orthologues of LRRK2 and RAB7L1 act coordinately in an ordered genetic

25 t, as a physiological downstream effector of LRRK2 and RAB7L1.

26 r, we conclude that 14-3-3theta can regulate LRRK2 and reduce the toxicity of mutant LRRK2 through a

27 Our work suggests a merge of LRRK2 and SYNJ1 pathogenic pathways in deregulating SV t

28 Mutations in leucine-rich repeat kinase 2 (LRRK2) and alpha-synuclein lead to Parkinson's disease (

29 ing known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative col

30 's disease-related proteins-alpha-synuclein, LRRK2, and Parkin-alpha-synuclein might be a major link.

31 er, the interaction between alpha-synuclein, LRRK2, and the formation of alpha-synuclein inclusions r

32 We identify conserved residues within the LRRK2 ankyrin domain that are required for Rab29-mediate

33 Mutations in LRRK2 are a common cause of genetic Parkinson's disease

34 ase) and kinase activities, and mutations in LRRK2 are the major cause of autosomal-dominant familial

35 Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with increased risk for developing

36 Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of inherited Park

37 Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most commonly linked contributor to famil

38 results from the expression of mutant G2019S-LRRK2, as overexpression of WT-LRRK2 not only does not i

39 p-loop residues, as revealed by alignment of LRRK2 autophosphorylation sites with GTPases annotated i

40 ts in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats ex

41 Here, we demonstrate that LRRK2 binds to and directly phosphorylates HDAC3 at Ser-

42 only present in LRRK(-/-), not LRRK1(-/-) or LRRK2(-/-) brains, and it is accompanied by increases in

43 led the 3D structure of dimeric, full-length LRRK2 by combining domain-based homology models with mul

44 Recent reports suggest that LRRK2 can act to regulate the cellular catabolic process

45 LRRK2 can function as a protein kinase and mutations lea

46 gene encoding leucine-rich repeat kinase 2 (LRRK2) can cause Parkinson's disease (PD), and the most

47 LRRK2 carrier status was confirmed by bidirectional Sang

48 LRRK2 carrier status was confirmed by Sanger sequencing

49 Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinsonism with pleomo

50 Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset, autosomal dominant familial Par

51 ing a role for endogenous WSB1 in modulating LRRK2 cell toxicity.

52 Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial

53 a reveal that Rab29 is a master regulator of LRRK2, controlling its activation, localization, and pot

54 eta further reduced neurite length in G2019S-LRRK2 cultures.

55 ntrast, the expression of LRRK2 wild type or LRRK2 D1994A mutant (kinase dead) had no effect on mtDNA

56 G2019S-LRRK2 slightly increases, whereas WT-LRRK2 decreases, total levels of alpha-synuclein.

57 Furthermore in rodents, LRRK2 deficiency or inhibition leads to lysosomal pathol

58 LRRK2 dependent phosphorylation of human Rab10 and human

59 signaling defects at cilia may contribute to LRRK2-dependent pathologies.

60 Interestingly, we show that LRRK2 directly phosphorylates synaptojanin1 in vitro, re

61 LRRK2 directly phosphorylates these both in vivo and in

62 ibility to mitochondrial calcium overload in LRRK2-driven neurodegeneration, and suggest possible int

63 bitors, PF-06447475 and MLi-2, blocks G2019S-LRRK2 effects, suggesting that the G2019S-LRRK2 potentia

64 We found that expression of mutant LRRK2 elicited transcriptional upregulation of the mitoc

65 n of MCU conferred protection against mutant LRRK2-elicited dendrite shortening, as did inhibiting MC

66 2 were consistent with binding to Ala2016 in LRRK2 (equivalent to Ala147 in CHK1 10-point mutant stru

67 tially reduces inclusion formation in G2019S-LRRK2-expressing neurons, suggesting that LRRK2 influenc

68 reased alpha-synuclein aggregation in G2019S-LRRK2-expressing neurons.

69 LRRK2 expression levels rise after birth at a time when

70 Because LRRK2 expression levels rise during synaptogenesis and a

71 Here, we show that G2019S-LRRK2 expression, in both cultured neurons and dopaminer

72 , syntaxin-1A and Rab3, in the brain of this LRRK2 fly model.

73 nase domain of leucine-rich repeat kinase 2 (LRRK2) follow Parkinson's disease (PD) heritability.

74 We show that mutations that prevent LRRK2 from interacting with either Rab29 or GTP striking

75 either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, incl

76 How LRRK2 function is regulated is not well understood.

77 t genetic resource for further evaluation of LRRK2 function.

78 Here we provide evidence that LRRK2 functions together with a second PD-associated gen

79 We provide evidence suggesting that LRRK2 G2019S and SYNJ1 loss of function share a similar

80 igh glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic

81 Combining SYNJ1(+/-) and LRRK2 G2019S does not exacerbate SV endocytosis but impa

82 Importantly, treatment of LRRK2 G2019S expressing midbrain neurons or patient-deri

83 ere we show that the most common PD mutation LRRK2 G2019S impairs SV endocytosis in ventral midbrain

84 Expression of LRRK2 G2019S induced mtDNA damage in primary rat midbrai

85 pressing midbrain neurons or patient-derived LRRK2 G2019S LCLs with the LRRK2 kinase inhibitor GNE-79

86 were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%,

87 Previously, we found that LRRK2 G2019S mutation carriers have increased mitochondr

88 e effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variati

89 Two patients with the LRRK2 G2019S mutation were excluded from the final analy

90 otype can be unambiguously attributed to the LRRK2 G2019S mutation, the underlying mechanism(s) is un

91 ing for the 7 known AJ GBA mutations and the LRRK2 G2019S mutation.

92 In addition, human LRRK2 G2019S patient-derived lymphoblastoid cell lines (

93 m Parkinson's disease (PD) patients carrying LRRK2 G2019S variants to controls identified significant

94 Expression of LRRK2 G2019S, the most common pathological mutation, pro

95 These findings support the hypothesis that LRRK2 G2019S-induced mtDNA damage is LRRK2 kinase activi

96 examine the role of LRRK2 kinase function in LRRK2 G2019S-mediated mtDNA damage, using both genetic a

97 utes to dendritic retraction elicited by the LRRK2-G2019S and -R1441C mutations.

98 The PD LRRK2-G2019S associated profile was positively matched w

99 hippocampus, we find that overexpression of LRRK2-G2019S increases basal synaptic efficiency through

100 ns (SPNs), we tested the hypothesis that the LRRK2-G2019S mutation would alter development of excitat

101 RRK2 overexpression, we used mice expressing LRRK2-G2019S or D2017A (kinase-dead) knockin mutations.

102 riation in the leucine-rich repeat kinase 2 (LRRK2) gene is associated with risk of familial and spor

103 The Leucine rich repeat kinase 2 (LRRK2) gene is genetically and biochemically linked to s

104 or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and r

105 Berber families with Parkinson's disease and LRRK2 Gly2019Ser (150 patients and 103 unaffected family

106 Berber families with Parkinson's disease and LRRK2 Gly2019Ser (with both affected and unaffected fami

107 4 unrelated Arab-Berber individuals who were LRRK2 Gly2019Ser carriers (seven with early-onset diseas

108 ta from another cohort of unrelated Tunisian LRRK2 Gly2019Ser carriers for subsequent locus-specific

109 eplicated the findings in separate series of LRRK2 Gly2019Ser carriers originating from Algeria, Fran

110 In a cohort of unrelated Arab-Berber LRRK2 Gly2019Ser carriers, subsequent association mappin

111 ression in human striatal tissues and murine LRRK2 Gly2019Ser cortical neurons.

112 namin-3 localisation was perturbed in murine LRRK2 Gly2019Ser cortical neurons.

113 ariability in DNM3 modifies age of onset for LRRK2 Gly2019Ser parkinsonism and informs disease-releva

114 fy genetic variability that directly affects LRRK2 Gly2019Ser penetrance.

115 that the R1441C mutation located within the LRRK2 GTPase domain induces the enhanced phosphorylation

116 Our model reveals dimeric LRRK2 has a compact overall architecture with a tight, m

117 LRRK2 has been implicated in numerous cellular processes

118 LRRK2 has guanosine triphosphatase (GTPase) and kinase a

119 s disease gene leucine-rich repeat kinase 2 (LRRK2) has been implicated in a number of processes incl

120 Leucine-rich repeat kinase 2 (LRRK2) has been linked to several clinical disorders inc

121 We found that rats expressing G2019S-LRRK2 have exacerbated dopaminergic neurodegeneration an

122 e mutations in Leucine-rich repeat kinase 2 (LRRK2) have been linked to Parkinson's disease (PD), the

123 oci, including leucine-rich repeat kinase 2 (LRRK2), have been identified.

124 eal a previously unknown regulatory role for LRRK2 in CX3CR1 signalling and suggest that an increase

125 RRK2, we expressed human wild-type or R1441C LRRK2 in dopaminergic neurons of Drosophila and observe

126 dies, co-expression of SP1 and mutant G2019S-LRRK2 in double transgenic Drosophila increased survival

127 rlie the diverse pathologies associated with LRRK2 in humans and in animal models.

128 Increasing evidence supports a role of LRRK2 in modulating microglial activity, of which Lrrk2-

129 These results implicate LRRK2 in primary ciliogenesis and suggest that Rab-media

130 Additional cell-based studies implicated LRRK2 in the AP-3 complex-related intracellular traffick

131 Despite the role of LRRK2 in the pathogenesis of PD, little is known about i

132 role of the different domains of full-length LRRK2 in the pathogenesis of PD.

133 dominantly interacted with the C-terminus of LRRK2, including kinase domain.

134 Co-expression of SP1 with LRRK2 increased LRRK2-induced cytoplasmic aggregation in

135 Here, we show that expression of G2019S-LRRK2 increases alpha-synuclein mobility and enhances ag

136 ntified 36 candidate interactors that modify LRRK2 induced toxicity in the Drosophila eye.

137 Co-expression of SP1 with LRRK2 increased LRRK2-induced cytoplasmic aggregation in cultured cells.

138 Expression of SP1 protects against G2019S-LRRK2-induced dopamine neuron loss and reduced LRRK2 pho

139 stigated whether 14-3-3s can regulate mutant LRRK2-induced neurite shortening and kinase activity.

140 g ERK1/2 conferred protection against mutant LRRK2-induced neurite shortening.

141 dings demonstrate that SP1 attenuates mutant LRRK2-induced PD-like phenotypes and plays a neural prot

142 Moreover, SP1 also attenuated mutant LRRK2-induced toxicity and reduced LRRK2 kinase activity

143 9S-LRRK2-expressing neurons, suggesting that LRRK2 influences alpha-synuclein inclusion formation by

144 cation of Rab10 phosphorylated at Thr73 as a LRRK2 inhibition marker in human PBMCs strongly support

145 acute inhibition of LRRK2 with two distinct LRRK2 inhibitor compounds reduced Rab10-Thr73 phosphoryl

146 nuclear blood cells (PBMCs) treated with the LRRK2 inhibitor Lu AF58786 a number of putative biomarke

147 To support clinical development of LRRK2 inhibitors as disease-modifying treatment in PD bi

148 tures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selec

149 ase progression, our team set out to develop LRRK2 inhibitors to test this hypothesis.

150 gment hit-derived arylpyrrolo[2,3-b]pyridine LRRK2 inhibitors underwent structure-guided optimization

151 ssessment of surrogate binding affinity with LRRK2 inhibitors.

152 ne stimulated human PBMCs using two distinct LRRK2 inhibitors.

153 using co-immunoprecipitation, we found that LRRK2 interacted with synphilin-1 (SP1), a cytoplasmic p

154 LRRK2 interacted with the N-terminus of SP1 whereas SP1

155 We identify WSB1 as a LRRK2 interacting protein.

156 contrast, Nrf2 sequestered misfolded diffuse LRRK2 into more insoluble and homogeneous inclusion bodi

157 We hypothesize that LRRK2 is a key modulator of microglial inflammatory resp

158 LRRK2 is a multi-domain Roco protein, harbouring kinase

159 e of inherited Parkinson's disease (PD), and LRRK2 is a risk factor for idiopathic PD.

160 LRRK2 is expressed by both neurons and microglia, the re

161 LRRK2 is suggested to be involved in a wide variety of c

162 ng from the most frequent G2019S mutation in LRRK2 is the key to this impairment.

163 The G2019S mutation in LRRK2 is the most common known genetic cause of PD.

164 Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein containing two ca

165 Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a

166 en this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting

167 is that LRRK2 G2019S-induced mtDNA damage is LRRK2 kinase activity dependent, uncovering a novel path

168 ed mutant LRRK2-induced toxicity and reduced LRRK2 kinase activity in cultured cells.

169 mpounds targeting this process by inhibiting LRRK2 kinase activity may slow progression of PD-associa

170 main suggest an intramolecular mechanism for LRRK2 kinase activity regulation.

171 The ability of 14-3-3theta to reduce LRRK2 kinase activity required direct binding of 14-3-3t

172 Chemical inhibition of LRRK2 kinase activity resulted in the stimulation of mac

173 endocytosis can be rescued by inhibition of LRRK2 kinase activity.

174 tivity, we examined 14-3-3theta's effects on LRRK2 kinase activity.

175 s the G2019S LRRK2 mutation that upregulates LRRK2 kinase activity.

176 Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1)

177 Here, we examine the role of LRRK2 kinase function in LRRK2 G2019S-mediated mtDNA dam

178 evels in upcoming clinical trials evaluating LRRK2 kinase inhibition as a disease-modifying treatment

179 Blocking or reversing mtDNA damage via LRRK2 kinase inhibition or other therapeutic approaches

180 r patient-derived LRRK2 G2019S LCLs with the LRRK2 kinase inhibitor GNE-7915, either prevented or res

181 ner, highlighting the therapeutic promise of LRRK2 kinase inhibitors in the treatment of PD.

182 Acute exposure to LRRK2 kinase inhibitors normalized activity, supporting

183 ion, treatment of primary mouse neurons with LRRK2 kinase inhibitors, PF-06447475 and MLi-2, blocks G

184 Potent LRRK2 kinase inhibitors, which are being developed for c

185 c cell models in the presence and absence of LRRK2 kinase inhibitors.

186 pein in G2019S-LRRK2 neurons was reversed by LRRK2 kinase inhibitors.

187 This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on phys

188 Parkinson's disease predisposing LRRK2 kinase phosphorylates a group of Rab GTPase protei

189 uman LRRK2 on the same residues as the human LRRK2 kinase.

190 our murine model, cortical Tat injection in LRRK2 knock-out (KO) mice results in significantly dimin

191 bstantially higher in microglia derived from Lrrk2 knockout (Lrrk2(-/-)) mice.

192 striatal projection neurons (SPNs) of adult LRRK2 knockout mice and that adult animals exhibit no de

193 LPS-induced inflammation in the striatum of Lrrk2(-/-) knockout mice with Cx3cr1 heterozygous and ho

194 Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to late-onset, autosomal dominant Parkinson'

195 In mice, deficiency of either RAB7L1 or LRRK2 leads to prominent age-associated lysosomal defect

196 Recent evidence has suggested a role of LRRK2, linked to the most frequent familial PD, in regul

197 is not clear but could provide insight into LRRK2-linked disease.

198 The pathogenesis of LRRK2-linked Parkinson's disease (PD) is not fully under

199 arkinson's disease (PD) and variation at the LRRK2 locus contributes to the risk for idiopathic PD.

200 the genetic burden arising from human mutant LRRK2 manifests as early pathophysiological changes to d

201 eplication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD.

202 Our results suggest LRRK2 may be involved in a wide variety of cellular proc

203 findings support the hypothesis that G2019S-LRRK2 may increase the progression of pathological alpha

204 r findings suggest that aberrant function of LRRK2 may lead to destabilization of neural circuits.

205 ut of Rab29 in A549 cells reduces endogenous LRRK2-mediated phosphorylation of Rab10.

206 ntal toxicity administered to mutant knockin LRRK2 mice over half their life span, with observable an

207 f primary neurons from BAC transgenic G2019S-LRRK2 mice returned back to wild-type levels.

208 neuronal cultures from BAC transgenic R1441G-LRRK2 mice.

209 er in microglia derived from Lrrk2 knockout (Lrrk2(-/-)) mice.

210 oss of Cx3cr1 restored the responsiveness of Lrrk2(-/-) microglia to LPS stimulation.

211 docytic defect, however, was not observed in LRRK2 mutant neurons from the neocortex (hereafter, cort

212 However, the mechanism whereby LRRK2 mutants contribute to nigral vulnerability remains

213 Elevated MCU and MICU1 were also observed in LRRK2-mutated patient fibroblasts, along with increased

214 's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease.

215 gic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's diseas

216 LRRK2 mutation carriers with manifest Parkinson's diseas

217 sease, p=0.02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinson's diseas

218 In the first study, LRRK2 mutation carriers with or without manifest Parkins

219 We included LRRK2 mutation carriers with or without manifest Parkins

220 serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and ind

221 duals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's dis

222 LRRK2 mutation carriers without manifest Parkinson's dis

223 Nine LRRK2 mutation carriers without manifest Parkinson's dis

224 th sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET

225 e obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Pa

226 we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Pa

227 In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parki

228 our data show how the most common PD-causing LRRK2 mutation dramatically alters excitatory synaptic a

229 ost common genetic cause of PD is the G2019S LRRK2 mutation that upregulates LRRK2 kinase activity.

230 Leucine-rich repeat kinase 2 (LRRK2) mutation 6055G-->A (Gly2019Ser) accounts for roug

231 The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and G

232 LRRK2 mutations are the most common genetic cause of Par

233 We found that PD-linked LRRK2 mutations increased dendritic and mitochondrial ca

234 these results demonstrate that PD-associated LRRK2 mutations perturb lysosome function in a kinase-de

235 LRRK2 mutations produce end-stage Parkinson's disease (P

236 king down endogenous WSB1 exacerbates mutant LRRK2 neuronal toxicity in neurons and the Drosophila mo

237 Knockdown of SP1 by siRNA enhanced LRRK2 neuronal toxicity.

238 of neurite shortening by difopein in G2019S-LRRK2 neurons was reversed by LRRK2 kinase inhibitors.

239 mutant G2019S-LRRK2, as overexpression of WT-LRRK2 not only does not increase formation of inclusions

240 elation with the enhanced CX3CR1 expression, Lrrk2-null microglia migrated faster and travelled longe

241 to the attenuated inflammatory responses in Lrrk2-null microglia.

242 in modulating microglial activity, of which Lrrk2-null rodent microglia display less inflammatory re

243 It is however unknown how LRRK2 oligomerization is regulated.

244 omplex (ROC) domain in this family] of human LRRK2 on the same residues as the human LRRK2 kinase.

245 In this study, we found that the ameba LRRK2 ortholog ROCO4 phosphorylates the GTPase domain [t

246 mvent experimental confounds associated with LRRK2 overexpression, we used mice expressing LRRK2-G201

247 t cortical neurons caused by two PARK genes: LRRK2 (PARK8) and SYNJ1 (PARK20).

248 us (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Park

249 might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of no

250 haplotype tag for which the median onset of LRRK2 parkinsonism in GG carriers was 12.5 years younger

251 e data demonstrate a role for WSB1 in mutant LRRK2 pathogenesis, and suggest involvement in Lewy body

252 on contributes to dendritic injury in mutant LRRK2 pathogenesis.SIGNIFICANCE STATEMENT Cognitive dysf

253 However, the effect of LRRK2 pathogenic mutations that cause Parkinson's diseas

254 LRRK2 pathophysiology remains unclear, but reduced dopam

255 ator, RILPL1 specifically interacts with the LRRK2-phosphorylated forms of Rab8A and Rab10, whereas R

256 eported that Parkinson's disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conser

257 RK2-induced dopamine neuron loss and reduced LRRK2 phosphorylation in double transgenic fly brains.

258 9S-LRRK2 effects, suggesting that the G2019S-LRRK2 potentiation of inclusion formation depends on its

259 Specifically, LRRK2 promoted the deacetylation of Lys-5 and Lys-12 on

260 We show that LRRK2 promotes cap-dependent translation and identify Fu

261 by showing that a third PD-related protein, LRRK2, promotes Miro removal by forming a complex with M

262 he multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause o

263 LRRK2-pSer935 HEK293 IC50 data for 22 were consistent wi

264 of target engagement was demonstrated, with LRRK2-pSer935 IC50 values for 22 in mouse brain and kidn

265 with apparent IC50's equivalent to IC50's on LRRK2-pSer935.

266 Pathogenic LRRK2 R1441G/C and Y1699C mutants that promote GTP bindi

267 interplay amongst these factors using mutant LRRK2(R1441G) (leucine-rich-repeat-kinase-2) knockin mic

268 nesis in fibroblasts derived from pathogenic LRRK2-R1441G knock-in mice.

269 highest in dorsal striatum, suggesting that LRRK2 regulates development of striatal circuits.

270 Mutations in LRRK2 represent the most common known genetic cause of P

271 action screen in the fly brain confirms that LRRK2 robustly interacts with numerous SV proteins, incl

272 Further, we demonstrate that blocking LRRK2's kinase activity, with the potent and selective i

273 on genetic cause of Parkinson's disease, but LRRK2's normal physiological role in the brain is unclea

274 Among the phospho-site hits were known LRRK2 sites as well as two phospho-sites on human Rab10

275 Overexpression of G2019S-LRRK2 slightly increases, whereas WT-LRRK2 decreases, to

276 Moreover, LRRK2 stimulated nuclear translocation of HDAC3 via the

277 ur findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rab

278 rs; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of su

279 usly identify a subset of Rab GTPases as key LRRK2 substrates.

280 Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased

281 In LRRK2, this paradigm may be reversed, as the kinase doma

282 late LRRK2 and reduce the toxicity of mutant LRRK2 through a reduction of kinase activity.

283 WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRR

284 stsynaptic knockdown of the fly homologue of LRRK2 thwarts retrograde, homeostatic synaptic compensat

285 rization (GAD), while recent reports suggest LRRK2 to exist under a monomeric and dimeric form in viv

286 ficial chromosome transgenic mouse models of LRRK2 to explore potential nonmotor mechanisms of PD.

287 Here, we show that Rab29 recruits LRRK2 to the trans-Golgi network and greatly stimulates

288 Since G2019S-LRRK2 toxicity is likely mediated through increased kina

289 ic overexpression of either the fly or human LRRK2 transgene induces a retrograde enhancement of pres

290 gra pars compacta dopamine neurons in R1441C LRRK2 transgenic rats reveal an age-dependent reduction

291 LRRK2 ultimately promoted 6-OHDA-induced cell death via

292 To explore the function of LRRK2 variants in vivo, we performed mass spectrometry a

293 Pathogenic LRRK2 variants mapping to different functional domains i

294 In analogy with a bacterial homologue, LRRK2 was proposed to act as a GTPase activated by dimer

295 the R1441C mutation in the GTPase domain of LRRK2, we expressed human wild-type or R1441C LRRK2 in d

296 ritic/neuritic shortening elicited by mutant LRRK2, whereas expression of a constitutively active mut

297 ission in cortical neurons expressing mutant LRRK2, which occurs before the well-characterized phenot

298 ession reduced the kinase activity of G2019S-LRRK2, while difopein promoted the kinase activity of G2

299 In contrast, the expression of LRRK2 wild type or LRRK2 D1994A mutant (kinase dead) had

300 n-stimulated human PBMCs acute inhibition of LRRK2 with two distinct LRRK2 inhibitor compounds reduce

301 Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for