ライフサイエンスコーパス: LRRK2

1 tenuates neurodegeneration induced by G2019S LRRK2.

2 protein in the brain relative to endogenous LRRK2.

3 c/charged residues in the assembly of active LRRK2.

4 imary cilia formation, similar to pathogenic LRRK2.

5 drives the dynamic activation of full-length LRRK2.

6 plasma membrane-anchored Rab10 than soluble LRRK2.

7 velopment of PD-related phenotypes linked to LRRK2.

8 may be important for additional functions of LRRK2.

9 s conformational dynamics in the G domain of LRRK2.

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

11 are the most common pathogenic mutations of LRRK2.

12 iduals with high-confidence pLoF variants in LRRK2.

13 014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesti

14 e sought to characterize the cell biology of LRRK2 activation.

15 erves as a conformational switch that drives LRRK2 activation.

16 Dominant PD-associated LRRK2 alleles may suppress EPAC-1 activity, further rest

17 association studies have identified dominant LRRK2 alleles that predispose their carriers to late-ons

18 ility to mycobacterial infection, suggesting LRRK2 also controls immunity.

19 e did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for

20 was strongly up-regulated in the absence of LRRK2 and down-regulated in its presence.

21 riers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a D

22 in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study fro

23 examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parki

24 Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly

25 and glucose impairment) on the phenotype of LRRK2 and GBA Parkinson's disease (PD), and on the preva

26 Mutations in LRRK2 and GBA1 are common genetic risk factors for Parki

27 a mechanistic and therapeutic convergence of LRRK2 and GCase in neurons derived from patients with PD

28 High expression of LRRK2 and its substrate Rab10 occurs in phagocytic cells

29 We showed that hWT-LRRK2 and LRRK2-G2019S bind to the a1 subunit of vATPase

30 ivator, and it drives accumulation of active LRRK2 and phosphorylated Rab10 on mitochondria.

31 Conversely, in the absence of LRRK2 and Rab8A, damaged endolysosomes are targeted to l

32 analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, fami

33 nderstanding the structures and functions of LRRK2 and suggest the potential utility of LRRK2 kinase

34 7 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs),

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

36 eport the structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRR

37 e role of PD-associated genes, such as SNCA, LRRK2, and CHCHD2, in mitochondrial dysfunction and thei

38 Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability a

39 ts carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplicatio

40 ement, uncovering an unexpected function for LRRK2, and providing a new link between membrane damage

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

42 Mutations in both PRKN and LRRK2 are known causes of Parkinson's disease (PD).

43 Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Pa

44 e encoding for leucine-rich repeat kinase 2 (LRRK2) are a common cause of hereditary Parkinson's dise

45 Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of late-onset, autosoma

46 Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson

47 Human genetics studies have linked LRRK2 as a major genetic contributor to familial and spo

48 results suggest an important role of mutant LRRK2 as a negative regulator of lysosomal GCase activit

49 These data support a model in which LRRK2 associates with and dissociates from distinct memb

50 Genetic variation in LRRK2 associates with the susceptibility to Parkinson's

51 rystal structure of the WD40 domain of human LRRK2 at 2.6- angstrom resolution, which reveals a seven

52 lysis, we reveal a 14- angstrom structure of LRRK2 bearing a pathogenic mutation that oligomerizes as

53 nd an atomic model of microtubule-associated LRRK2 built using a reported cryo-electron tomography in

54 Our findings suggest that LRRK2 can act as a roadblock for microtubule-based motor

55 o phosphorylate Rab substrates; if anchored, LRRK2 can modify misdelivered Rab substrates that then b

56 no differences in clinical features between LRRK2 carriers and non-carriers.

57 des and prediabetes were more frequent among LRRK2 carriers, MS does not seem to influence GBA and LR

58 Mutations in LRRK2 cause autosomal dominant and sporadic Parkinson's

59 Pathogenic LRRK2 causes the centrosomal accumulation not only of ph

60 nduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and 2 validation studies o

61 l studies have established that mutations in LRRK2 confer susceptibility to mycobacterial infection,

62 athogenic mutant I2020T, spontaneously forms LRRK2-decorated microtubules in cells, while the wild ty

63 ate previously unappreciated consequences of LRRK2-dependent mitochondrial defects in controlling inn

64 was observed and correlated with measures of LRRK2 dephosphorylation.

65 impairing RAB8A function, pathogenic G2019S LRRK2 deregulates endolysosomal transport and endocytic

66 LRRK2 disease mutations mostly abolish the interaction w

67 Genome Atlas Breast Cancer Project, somatic LRRK2 DNA sequence information was obtained for 93 cases

68 Leucine-rich repeat kinase 2 (LRRK2) encodes a complex protein that includes kinase an

69 ight be through a lncRNA-regulated effect on LRRK2 expression because LINC02555 has previously been s

70 C02555 has previously been shown to regulate LRRK2 expression.

71 suggesting that it is independent of mutant LRRK2 expression.

72 his interference and reduce the formation of LRRK2 filaments in cells, whereas inhibitors that stabil

73 Despite the fundamental importance of LRRK2 for understanding and treating Parkinson's disease

74 LRRK2 functions as both a kinase and GTPase, and PD-link

75 Recent study has shown that LRRK2 G-domain cycles between monomeric and dimeric conf

76 minergic nigral and cortical neurons of both LRRK2 G2019S and idiopathic PD patients exhibit abnormal

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

78 uripotent stem cells of PD patients carrying LRRK2 G2019S are reported to have several phenotypes com

79 owed a reduction of mature autophagosomes in LRRK2 G2019S fibroblasts, which was rescued by LRRK2 spe

80 There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic a

81 In the LRRK1/2 double knockout or LRRK2 G2019S knockin, the dopaminergic axon bundle in th

82 ingle knockout, LRRK1/2 double knockout, and LRRK2 G2019S knockin, the postcrossing spinal cord commi

83 We previously discovered that the LRRK2 G2019S mutation causes mitochondrial DNA (mtDNA) d

84 to be decreased in fibroblasts carrying the LRRK2 G2019S mutation compared to cells isolated from he

85 cell biological signatures specific for the LRRK2 G2019S mutation producing Parkinson's disease (PD)

86 ed homology directed repair to introduce the LRRK2 G2019S mutation, as well as a truncation of the LR

87 ased in PD patient-derived immune cells with LRRK2 G2019S mutations as compared with controls.

88 We found that, similar to humans, marmoset LRRK2 G2019S resulted in elevated kinase activity.

89 Dopaminergic neurons of LRRK2 G2019S transgenic and LRRK2 -/- mice display decre

90 Here, we show that LRRK2 G2019S-induced neurodegeneration is critically dep

91 er dopaminergic differentiation demonstrated LRRK2 G2019S-mediated increased intracellular ROS, decre

92 events aberrant protein synthesis and blocks LRRK2 G2019S-mediated neurodegeneration in Drosophila an

93 of PD that expresses physiological levels of LRRK2 G2019S.

94 Leucine-rich repeat kinase 2 (LRRK2) G2019S is a relatively common mutation, associate

95 We showed that hWT-LRRK2 and LRRK2-G2019S bind to the a1 subunit of vATPase, which is

96 The expression of LRRK2-G2019S or hWT-LRRK2 inhibited autophagosome produc

97 hway in primary neurons expressing the human LRRK2-G2019S or LRKK2-R1441C mutant or the human wild-ty

98 acrophages from PD patients where pathogenic LRRK2 gain-of-function mutations result in the accumulat

99 For the LRRK2 gene an enrichment of nonsynonymous variants was o

100 The LRRK2 gene, coding for leucine rich repeat kinase 2 (LRR

101 Our studies provide a novel LRRK2 gene-MPTP interaction PD mouse model, and a useful

102 tations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkin

103 nigra; and (b) leucine-rich repeat kinase 2 (LRRK2) gene identified patient induced pluripotent stem

104 ative pathology to understand how the G2019S LRRK2 genetic risk factor affects the spread and toxicit

105 K2-R1441C mutant or the human wild-type (hWT-LRRK2) genomic locus.

106 hat conformational dynamics is important for LRRK2 GTPase activity and that the N1437H mutation impai

107 s with neuronal-specific expression of human LRRK2 harboring the most common G2019S mutation.

108 We thus hypothesize that LRRK2 harbors a classical protein kinase switch mechanis

109 LRRK2 has been associated with sporadic and familial for

110 LRRK2 has been proposed to function in membrane traffick

111 At least part of why LRRK2 has been so difficult to define is that it appears

112 Despite extensive efforts, LRRK2 has proved remarkably evasive with regard to attem

113 ssociated gene leucine-rich repeat kinase 2 (LRRK2) has been studied extensively in the brain.

114 disease gene, leucine-rich repeat kinase 2 (LRRK2), has an unexpected role in growth cone-growth con

115 ion control and Ca(2+) homeostasis in G2019S LRRK2 human dopamine neurons, which potentially contribu

116 of Frizzled3 at T598 and can be regulated by LRRK2 in a kinase activity-dependent way.

117 These results demonstrate the importance of LRRK2 in lysosomal biology, as well as the critical role

118 We demonstrate that loss of LRRK2 in macrophages induces elevated basal levels of ty

119 the present work, the molecular mechanism of LRRK2 in the control of neurogenesis or gliogenesis was

120 The mutant LRRK2 increased kinase activity was reduced by pharmacol

121 Our study further demonstrates that G2019S LRRK2-induced dopaminergic neurodegeneration critically

122 n together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism

123 In this model, G2019S LRRK2 induces the robust degeneration of substantia nigr

124 The expression of LRRK2-G2019S or hWT-LRRK2 inhibited autophagosome production, whereas LRRK2-

125 oncerns(5-8), the biological consequences of LRRK2 inhibition have not been well characterized in hum

126 ed and synthesized novel benzothiazole-based LRRK2 inhibitors and showed that they can modulate the W

127 potential new avenues for the application of LRRK2 inhibitors in demyelinating diseases in which olig

128 king dephosphorylation seen upon addition of LRRK2 inhibitors.

129 tially be targeted by new therapies, such as LRRK2 inhibitors.

130 LRRK2 is a kinase expressed in striatal spiny projection

131 LRRK2 is a multi-domain protein containing a kinase and

132 The C-terminal region of LRRK2 is a Trp-Asp-40 (WD40) domain with poorly defined

133 the Parkinson's disease (PD)-related kinase LRRK2 is activated in macrophages by pathogen- or steril

134 Importantly, mitochondrially anchored LRRK2 is much less capable of phosphorylating plasma mem

135 LRRK2 is quite unusual in that the highly conserved Phe

136 We show that the catalytic half of LRRK2 is sufficient for filament formation and blocks th

137 9S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of familial Parkinson's disease

138 9S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinson's disease (PD) and

139 Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein with both a Ras of

140 Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein, and LRRK2 mutants

141 Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatme

142 Leucine rich repeat kinase 2 (LRRK2) is an enigmatic enzyme and a relevant target for

143 Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Par

144 ne, coding for leucine rich repeat kinase 2 (LRRK2), is a key player in the genetics of Parkinson's d

145 urement of mtDNA damage is a "surrogate" for LRRK2 kinase activity and consequently of kinase inhibit

146 Assessment of full-length LRRK2 kinase activity by measuring phosphorylation of Ra

147 disease(3,4), suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strateg

148 Inhibition of LRRK2 kinase activity results in increased GCase activit

149 uses mitochondrial DNA (mtDNA) damage and is LRRK2 kinase activity-dependent.

150 autolysosome maturation is not dependent on LRRK2 kinase activity.

151 G2019S is hypothesized to increase LRRK2 kinase activity.

152 Mutations in the LRRK2 kinase are the most common cause of familial Parki

153 We propose that the conformation of the LRRK2 kinase domain regulates its interactions with micr

154 19S mutation, as well as a truncation of the LRRK2 kinase domain, into marmoset embryonic and induced

155 orylation of Rab10, mimicking the effects of LRRK2 kinase inhibition in promoting cargo recycling.

156 Both Rab10 knockdown and LRRK2 kinase inhibition potently suppress the maturation

157 proposed as target engagement biomarkers for LRRK2 kinase inhibition.

158 rom mutant LRRK2 mice, and are reverted upon LRRK2 kinase inhibition.

159 In contrast, treatments with an LRRK2 kinase inhibitor significantly reduced the dopamin

160 he treatment of Parkinson's disease (PD) and LRRK2 kinase inhibitors are currently being tested in ea

161 f LRRK2 and suggest the potential utility of LRRK2 kinase inhibitors in treating PD patients with WD4

162 Following treatment with multiple classes of LRRK2 kinase inhibitors, a full reversal of mtDNA damage

163 Using the two selective and potent LRRK2 kinase inhibitors, MLi-2 and PF-06447475, we demon

164 e implications for the design of therapeutic LRRK2 kinase inhibitors.

165 activity and provide an extended profile of LRRK2 kinase modulation in clinical studies.

166 LRRK2 kinase mutations cause familial Parkinson's diseas

167 ved in secretory and endocytic recycling are LRRK2 kinase substrates in vivo However, the effects of

168 LRRK2 knockdown caused nuclear lamina abnormalities and

169 e interaction with lamin A/C and, similar to LRRK2 knockdown, cause disorganization of lamin A/C and

170 Altered innate immune gene expression in Lrrk2 knockout (KO) macrophages is driven by a combinati

171 ated primary macrophages derived from WT and Lrrk2 knockout mice.

172 Growth cones from either LRRK2 knockout or G2019S knockin mice showed altered int

173 While Lrrk2 KO mice can control Mycobacterium tuberculosis (Mt

174 late-onset patients were genotyped with the LRRK2 'Kompetitive' allele-specific polymerase chain rea

175 rovides a robust rodent preclinical model of LRRK2-linked PD and nominates kinase inhibition and modu

176 Genetic variation at the LRRK2 locus was associated with survival in PSP.

177 LRRK2-mediated centrosomal cohesion and ciliogenesis alt

178 These data suggest that the LRRK2-mediated centrosomal cohesion and ciliogenesis def

179 Conversely, the pathogenic LRRK2-mediated ciliogenesis defects correlate with the c

180 odeficient RAB8A variants rescues the G2019S LRRK2-mediated effects on endolysosomal membrane traffic

181 e substrates in vivo However, the effects of LRRK2-mediated phosphorylation of these substrates on me

182 Overexpression of PPM1H suppressed LRRK2-mediated Rab phosphorylation.

183 ing axis in the endolysosomal system whereby LRRK2-mediated Rab10 phosphorylation stalls vesicle fast

184 Cortical neurons from G2019S-LRRK2 mice showed an increased vulnerability to stress i

185 as well as in primary astrocytes from mutant LRRK2 mice, and are reverted upon LRRK2 kinase inhibitio

186 t that was milder than for the mutant G2019S-LRRK2 mice.

187 ergic neurons of LRRK2 G2019S transgenic and LRRK2 -/- mice display decreased circularity of the nucl

188 Mutation of one of these abolishes LRRK2 microtubule-association.

189 ecific PD gene target agents (such as GBA or LRRK2 modifiers) and other potential disease modifying d

190 Here we asked whether LRRK2 modifies inflammatory signaling and how this modif

191 onal motility, and our results indicate that LRRK2 modulates chemotaxis of microglia and macrophages.

192 These results indicate that LRRK2 modulates the expression of genes involved in muri

193 will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP

194 ere we define the translational landscape in LRRK2-mutant dopaminergic neurons derived from human ind

195 (LRRK2) is a large multidomain protein, and LRRK2 mutants are recognized risk factors for Parkinson'

196 anization of glutamatergic AMPA receptors in LRRK2 mutants.

197 Exploration of the genomic landscape of LRRK2-mutated carcinomas yielded frequent TP53 deactivat

198 LRRK2-mutated mammary carcinomas are enriched with stop-

199 e clinicopathologic features associated with LRRK2-mutated tumors.

200 Nonmanifesting LRRK2 mutation carriers had significantly higher levels

201 iomarker of PD risk modulation in pathogenic LRRK2 mutation carriers.

202 mental influences on disease pathogenesis in LRRK2 mutation carriers.

203 ate as a biomarker of resistance to PD among LRRK2 mutation carriers.

204 ex-matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct

205 mbines a sub-toxic MPTP insult to the G2019S-LRRK2 mutation.

206 cated, since 2 of the 5 most common familial LRRK2 mutations (G2019S and I2020T) are localized to the

207 ohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplicat

208 More important, breast cancers with LRRK2 mutations are associated with reduced patient surv

209 While PD-linked LRRK2 mutations can commonly induce neuronal damage in c

210 ics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls.

211 seen in this subset of tumors suggests that LRRK2 mutations may herald benefit from immune checkpoin

212 dings, for the first time, show that somatic LRRK2 mutations occur frequently in breast cancer, and t

213 Rodent models containing familial LRRK2 mutations often lack robust PD-like neurodegenerat

214 Overall, LRRK2 mutations reshaped synaptic structure and function

215 LRRK2 mutations, the most common genetic cause of Parkin

216 c (DA) neurons derived from PD patients with LRRK2 mutations.

217 gize with other neurotoxic effects caused by LRRK2 mutations.

218 broad role for leucine-rich repeat kinase 2 (LRRK2) mutations in familial and idiopathic PD has emerg

219 s and autophagy are critical determinants of LRRK2 neurodegeneration, opening up possibilities for fu

220 R) are translated more efficiently in G2019S LRRK2 neurons.

221 -PD, 70 GBA-PD, 196 healthy non-carriers, 55 LRRK2-NMC and 97 GBA-NMC participated in this study.

222 gher rates of prediabetes (p = 0.004), while LRRK2-NMC had higher triglyceride levels (p = 0.014).

223 posmia was significantly more common only in LRRK2 non-manifesting carriers (69 [36%] of 194 healthy

224 Finally, GBA but not LRRK2 non-manifesting carriers showed increased DAT stri

225 of 194 healthy controls vs 114 [55%] of 208 LRRK2 non-manifesting carriers; p=0.0003).

226 , we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in t

227 Loss of RAB8A mimicked the effects of G2019S LRRK2 on endolysosomal trafficking and decreased RAB7A a

228 thesis can modulate the pathogenic effect of LRRK2 on protein synthesis and thereby impact neuronal l

229 ed the role of leucine-rich repeat kinase 2 (LRRK2) on lysosome biology and the autophagy pathway in

230 sed GCase activity in DA neurons with either LRRK2 or GBA1 mutations.

231 rway to develop new therapeutics that target LRRK2 or glucocerebrosidase (GCase).

232 Expression of pathogenic G2019S LRRK2 or loss of RAB8A interfered with EGFR degradation

233 red with neurons overexpressing wild-type WT-LRRK2, or non-transgenic (nTg) neurons.

234 he first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China.

235 hogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A8

236 s shared Oxidative Stress Defense System and LRRK2 pathways with AD and PD, respectively.

237 from idiopathic patients (AHNPs) and mutant LRRK2 patients showed differences between both phenotype

238 Current LRRK2 PD animal models only partly reproduce the charact

239 f neurodegeneration in a Drosophila model of LRRK2 PD.

240 LRRK2-PD had higher levels of triglycerides (p = 0.015)

241 riers, MS does not seem to influence GBA and LRRK2-PD phenotype.

242 One hundred and four idiopathic PD, 40 LRRK2-PD, 70 GBA-PD, 196 healthy non-carriers, 55 LRRK2-

243 Ala) binds with high affinity to endogenous, LRRK2-phosphorylated Rab proteins, thereby blocking deph

244 LRRK2 phosphorylates a subset of Rab GTPases within thei

245 LRRK2 phosphorylates cytoplasmic PI(3,4,5)P3-positive GT

246 LRRK2 phosphorylates multiple RAB GTPases including RAB8

247 LRRK2 phosphorylation, and phosphorylation of the LRRK2

248 ophages includes CCR5, CD11b, and MHCII, and LRRK2-phosphorylation of Rab10 potently blocks EHBP1L1-m

249 HBP1L1 overexpression competitively inhibits LRRK2-phosphorylation of Rab10, mimicking the effects of

250 Our data indicate that LRRK2 plays an essential role in maintaining nuclear env

251 ionally, the roles of other PD genes such as LRRK2, PRKN, and VPS35 in the regulation of SVE are begi

252 The LRRK2 protein acts as a scaffold and induces Frizzled3 h

253 work defines a novel interaction between the LRRK2 protein and the vATPase a1 subunit and demonstrate

254 e findings demonstrate an important role for LRRK2 protein in regulation of mitochondrial clearance b

255 nvolving the robust destabilization of human LRRK2 protein in the brain relative to endogenous LRRK2.

256 generated mice, overexpressing mutant G2019S-LRRK2 protein in the brain, displayed a mild, age-depend

257 treated with a highly specific inhibitor of LRRK2 protein kinase activity.

258 Mutations that activate LRRK2 protein kinase cause Parkinson's disease.

259 t heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly ass

260 inhibited autophagosome production, whereas LRRK2-R1441C induced a decrease in autophagosome/lysosom

261 ubunit of vATPase, which is abolished by the LRRK2-R1441C mutation, leading to a decrease in a1 prote

262 ed vATPase a1 protein levels and rescued the LRRK2-R1441C-mediated cellular phenotypes.

263 -2 and PF-06447475, we demonstrated that the LRRK2-R1441C-mediated decrease in autolysosome maturatio

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

265 LRRK2 recruits the Rab GTPase Rab8A to damaged endolysos

266 We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not

267 Altogether, this work indicates that LRRK2 regulates endolysosomal homeostasis by controlling

268 Our findings demonstrate that LRRK2 regulates growth cone-growth cone communication in

269 LRRK2 regulates various intracellular vesicular traffick

270 Although the precise mechanisms that control LRRK2 regulation and function are unclear, the importanc

271 e LRRK2 substrate Rab10 as a key mediator of LRRK2 regulation of GCase activity.

272 Although LRRK2-related Parkinson disease patients have a heighten

273 rations may serve as cellular biomarkers for LRRK2-related PD.

274 in the past decade, the precise function of LRRK2 remains largely unknown.

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

276 teins (ROC) of leucine rich repeat kinase 2 (LRRK2) result in an abnormal over-activation of its kina

277 ns-Golgi and activates it there, yet some of LRRK2's major Rab substrates are not on the Golgi.

278 Interestingly, mice overexpressing WT-LRRK2 showed a significant impairment that was milder th

279 e modeling, we determine the architecture of LRRK2, showing that the GTPase and kinase are in close p

280 s known to be important kinase substrates of LRRK2, shows enhancement of kinase activity by several d

281 Thus, PPM1H acts as a key modulator of LRRK2 signaling by controlling dephosphorylation of Rab

282 died protein phosphatase, PPM1H, counteracts LRRK2 signaling by specifically dephosphorylating Rab pr

283 In LRRK1 or LRRK2 single knockout, LRRK1/2 double knockout, and LRRK

284 number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be ta

285 this study was to evaluate the occurrence of LRRK2 somatic mutations in breast cancer and the clinico

286 cluding breast cancer, it is unknown whether LRRK2 somatic mutations occur and are associated with br

287 RK2 G2019S fibroblasts, which was rescued by LRRK2 specific kinase inhibition.

288 th and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex.

289 ndrially anchored, GTP-bound Rab29 is both a LRRK2 substrate and activator, and it drives accumulatio

290 We have identified the LRRK2 substrate Rab10 as a key mediator of LRRK2 regulat

291 phosphorylation, and phosphorylation of the LRRK2 substrate Rab10, have been proposed as target enga

292 clinical infection model also indicated that Lrrk2 subtly modifies the inflammatory response.

293 ht into the mechanisms and pathways allowing LRRK2 to act in this manner will have implications for o

294 Rab29 recruits LRRK2 to the trans-Golgi and activates it there, yet som

295 on's disease, but the mechanisms involved in LRRK2 toxicity in PD are yet to be fully understood.

296 x and substantia nigra pars compacta of aged LRRK2 transgenic animals revealed alterations in autopha

297 The exposure of LRRK2 transgenic mice to a sub-toxic dose of MPTP result

298 We found that LRRK2 translocates to the nucleus by binding to seven in

299 phenotypes were not observed in clones with LRRK2 truncation.

300 e 4.6 [SD 4.4] healthy controls vs 8.4 [7.3] LRRK2 vs 9.5 [9.2] GBA, p<0.0001 for both comparisons) a

301 cytosol; nevertheless, Rab29 only activates LRRK2 when it is membrane bound and GTP bound.