LRRK2 and Parkinson Disease

NEUROLOGICAL REVIEW

Justus C. Dächsel, PhD; Matthew J. Farrer, PhD

Objectives: To review the molecular genetics and func- Data Synthesis: Genetic mutations that predispose tional biology of leucine-rich repeat kinase 2 (LRRK2) PD are diagnostically useful in early or atypical pre- in parkinsonism and to summarize the opportunities and sentations. The molecular pathways identified suggest challenges to develop interventions for Parkinson dis- therapeutic interventions for Lrrk2 and idiopathic PD ease (PD) based on this genetic insight. and the rationale and opportunity to develop physi- ologically relevant biomarkers and experimental mod- Data Sources: Publications cited are focused on LRRK2 els with which to test them. biology between 2004 and March 2009. Conclusions: Both affected and asymptomatic LRRK2 Study Selection: Literature selected was based on origi- carriers now provide the opportunity to define the nal contributions, seminal observations, and thoughtful reviews. natural history of PD. This includes the frequency, penetrance, and rate of motor symptoms, nonmotor Data Extraction: Unless stated otherwise, data was pri- comorbidities, and their associated biomarkers. marily abstracted from peer-reviewed literature appear- ing on PubMed. Arch Neurol. 2010;67(5):542-547

ARKINSON DISEASE (PD) HAS herited parkinsonism reminiscent of traditionally been consid- L-DOPA–responsive late-onset PD ered a sporadic, neurodegen- allowed Funayama and colleagues7 to erative disorder.1 Epidemio- map a novel PARK locus (PARK8) to logical efforts have identified chromosome 12q12. Linkage mapping severalP environmental risk factors includ- localizes mutant genes based on the ing rural living, farming, well water, and coinheritance of genetic markers and pesticides,2 but twin studies of disease con- phenotypes in families over several gen- cordance have provided limited evidence erations. The PARK8 assignment was for a genetic etiology.3 Nevertheless, PD confirmed in Western Nebraska Family D is a heterogeneous, multifactorial syn- and German-Canadian Family A, and drome with age-associated penetrance for pathogenic amino acid substitutions which genetic susceptibility contributes to p.R1441C and p.Y1699C were subse- risk. In PD, there is evidence for familial quently identified in a novel gene, aggregation and historically there have leucine-rich repeat kinase 2 (LRRK2; been detailed descriptions of kindreds in Lrrk2).8 Genetic linkage in other families which parkinsonism appears to follow a with late-onset parkinsonism revealed mendelian pattern of inheritance.4,5 In the other mutations including Lrrk2 last 10 years, several chromosomal loci p.R1441G in familial and seemingly spo- (termed PARK), genes, and mutations have radic PD from the Basque region of been linked to familial parkinsonism northern Spain9 and Lrrk2 p.G2019S in through classic linkage approaches.6 The families from Norway, Ireland, Poland, fundamental molecular insights that have and the United States.10 Lrrk2 p.I2020T arisen predict disease susceptibility and was found to explain disease in the origi- provide both the rationale and tools to de- nal Sagamihara pedigree in Japan.11 velop novel therapeutic approaches. LRRK2 AND LEUCINE-RICH Author Affiliations: IDENTIFICATION OF PARK8 AND REPEAT KINASE 2 Laboratories of Neurogenetics, LRRK2: THE PREDOMINANT Department of Neuroscience, GENETIC RISK FACTOR FOR PD Morris K. Udall Parkinson’s The genomic region comprised by LRRK2 Disease Research Center of is relatively large. The gene encompasses Excellence, Mayo Clinic, In 2002, genetic linkage analysis of a approximately 144 kilobases with 51 ex- Jacksonville, Florida. Japanese family with dominantly in- ons. It encodes a 2527–amino acid pro-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 tein (286 KDa) termed leucine-rich repeat kinase 2 (Lrrk2) after 2 of its conserved domain structures, a leucine- rich repeat toward the N terminal of the protein and a kinase domain (MAPK) toward the C terminal. Several other conserved domain structures, including arma- dillo and ankyrin repeats, GTPase (Roc), and a C terminal of Roc spacer (COR) as well as WD40 repeats, have been recognized, and all are potentially associated with protein-protein interactions.12 The Lrrk2 kinase domain has been classified as a member of the tyrosine kinase–like subfamily whose members show sequence similarity to tyrosine and serine- threonine kinases.12 Serine or threonine residues now appear to be the major target for phosphorylation.13 Other members of this class initiate mitogen-activated protein kinase pathways where effector kinases activated in a mul- tistep cascade ultimately execute a response to extracel- lular stimuli. In Lrrk2, the combination of Roc-COR- MAPK motifs encoding 2 distinct but physically linked Figure. A “ribbon” model of the MAPK domain of Lrrk2. In catalytic domains enzymatic domains is highly conserved among verte- of protein kinases, a small N terminal lobe and a larger C terminal lobe are connected to form a cleft in which adenosine triphosphate and the protein brates and shares homology with the ROCO protein fam- substrate may react. The Lrrk2 MAPK activation segment is a ribbon of ily of receptor-interacting protein kinases. Receptor- protein from 2017 to 2042 amino acids of the large C terminal lobe interacting protein kinases are known for their (magenta). The region, defined by conserved tripeptide “hinges” DF/YG and involvement in cellular stress signaling and mediate their APE, serves to block substrate access to the catalytic site (yellow). Lrrk2 ␬ 2019S and 2020T side chains affect 1 hinge of the activation segment (blue), response through JNK, ERK, p38, and NF- B path- and the magnesium–adenosine triphosphate binding site is highlighted ways.14 Given the size, domain composition, and orga- (turquoise). The majority of protein kinases, including Lrrk2, require nization of Lrrk2, and the potential for protein-protein phosphorylation of the activation segment for activity. On phosphorylation, the activation segment is believed to adopt an active conformation, enabling interactions, it is likely to be part of a higher-molecular- substrate access and catalysis to take place. weight complex involved in cellular signaling. At a mini- mum, monomers of Lrrk2 protein dimerize similar to the conformation adopted by most protein kinases and Ras ratio, carriers have more than a 20-fold increase in dis- GTPases.15 ease risk.18 In the United States and Europe, the muta- The closest human homologue of LRRK2 is LRRK1 on tion is found in 0.5% to 2.0% of seemingly sporadic PD chromosome 15q26 (70% homology of Roc, COR, and and 5% of dominantly inherited familial parkinsonism.6 MAPK domains). The 2 proteins differ mostly in the or- Family-based studies show disease penetrance in Lrrk2 ganization of their N termini as Lrrk2 possesses several p.G2019S carriers is age dependent, increasing from about specific repeat structures absent in the Lrrk1 homo- 20% at age 50 years to 80% at age 70 years.10,19 Despite logue. Phylogenetic analysis suggests that LRRK2 origi- ascertainment bias in pedigree-based studies, the age- nated from gene duplication because Caenorhabditis el- associated cumulative incidence of seemingly sporadic egans and Drosophila melanogaster possess only 1 LRK-1 PD in clinic-based Lrrk2 carriers concurs.18 This is dra- gene.16 Thus, in vertebrates, Lrrk1 and Lrrk2 may have matically different from the incidence of PD in the gen- similar if not redundant functional activities. Intensive eral population, which is rare before age 50 years and may sequencing efforts have yet to reveal pathogenic LRRK1 reach 4% in subjects older than 80 years.1 Historically, mutations in familial parkinsonism.17 the Lrrk2 p.G2019S mutation is associated with 1 chromosome 12q12 haplotype inherited identical by de- LRRK2 PATHOGENIC MUTATIONS scent from 1 ancestral founder; most patients with Lrrk2 AND POLYMORPHIC RISK FACTORS: p.G2019S are genetically related, although there are some FAMILIES AND FOUNDERS exceptions.10,20 In North African Arab-Berbers, the major haplotype is shortest and most frequent, consistent More than 75 Lrrk2 coding substitutions have been de- with its origin in this ethnic group. Indeed, in this part scribed but not all contribute to the risk of parkinson- of the world and possibly throughout the Maghreb, more ism, or to the same degree. Indeed, genetic evidence for than one-third of all patients diagnosed with PD are Lrrk2 pathogenicity is only proven for p.R1441C, p.R1441G, p.G2019S carriers.18 Notably, about 15% of patients with p.Y1699C, p.G2019S, and p.I2020T substitutions (by link- Ashkenazi Jewish heritage have the same Lrrk2 p.G2019S age) and for p.R1628P and p.G2385R (by association) mutation.21,22 (http://www.genetests.org). While other sequence vari- In contrast, Lrrk2 p.R1628P and p.G2385R are the ants may be pathogenic, they might represent benign mu- most common susceptibility variants, which double dis- tations or polymorphisms. This is a critical distinction ease risk. Each is found in approximately 3% to 4% of in patient diagnosis and in interpreting Lrrk2 function. healthy subjects and 6% to 8% of patients, and each ap- Lrrk2 p.G2019S appears to be the most frequent patho- pears to have been inherited identical by descent from genic substitution and directly affects the “activation an ancient founder.23,24 While the genetic association of hinge” of the MAPK domain (Figure). In terms of an odds Lrrk2 p.R1628P with parkinsonism appears restricted to

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 the ethnic Chinese population, Lrrk2 p.G2385R has been main also requires intramolecular dimerization for opti- reported in clinical and community-based studies mal GTPase activity.15,39,40 throughout Asia, including Taiwan, Singapore, Korea, and A further limitation is that most assays focus on in vitro Japan.23-27 Lrrk2 p.R1629P is located within the COR do- autophosphorylation or artificial substrates, as few au- main that bridges the Roc and MAPK domains, whereas thentic Lrrk2 substrates have been nominated. These in- p.G2385R is located on the external surface of the C ter- clude threonine 558 of moesin, a member of the ERM/ minal WD40 “barrel.” merlin family that links plasma membrane receptor complexes to the microfilament cytoskeleton,41 and theo- LRRK2 IN THE BRAIN nine 37/46 of 4E-BP, a negative regulator of eIF4E- mediated protein translation that is critical in stress re- LRRK2 messenger RNA expression is found in most response and dopaminergic neuronal maintenance.42 gions, including nuclei affected in PD. Messenger RNA is However, validation in the brain is required and rel- especially abundant in dopamine-innervated areas and A9 evance to PD has not been established. midbrain dopaminergic neurons of the substantia nigra and Lrrk2 kinase activity seems to be the culprit in sev- is found in peripheral organs, including the heart, liver, eral cellular models where overexpression of Lrrk2 (wild kidney, lung, and leukocytes.28 However, the specificity of type or mutants) leads to aggregation and cellular tox- antibodies and different fixation techniques has ham- icity.43,44 Transfection of a Lrrk2 variant with deficient pered studies of protein expression (with fixation, Lrrk2 kinase activity (kinase “dead”) blocks the formation of antigens may be masked, their molecular interactions per- aggregates and seems to delay cellular death. While it re- turbed, or the complex may simply fall apart). Neverthe- mains unclear if Lrrk2 aggregation is a feature of PD, or less, overexpression of tagged protein expression in FLAG- a transfection artifact, the data suggest protein aggrega- Lrrk2 bacterial artificial chromosome mice provides a tion and/or clearance may be regulated by Lrrk2 kinase guide.29 Both Lrrk2 protein and messenger RNA levels ap- activity.45,46 pear high in the striatum, cortex, and cerebellum. LRRK2 In differentiated neuroblastoma or primary neuronal messenger RNA and protein levels also appear high in the cultures, and in the intact rodent central nervous sys- subventricular zone and dentate gyrus, with an active role tem, overexpression of Lrrk2 mutants induces a progres- in adult neurogenesis (H. Melrose, PhD, oral and written sive reduction in neuritic length and branching.47-49 In communication). Imaging studies suggest the in vivo neu- contrast, Lrrk2 knock down induced by RNA interfer- rochemical phenotype of Lrrk2 mutations is comparable ence, or overexpression of a Lrrk2 variant with defi- with idiopathic PD. However, the ability to assess asymp- cient kinase activity, confers increased neuritic length and tomatic carriers provides the most remarkable window into branching.47,50 In culture systems, overexpression of patho- disease onset and progression.30 Pathologically, more than genic Lrrk2 variants linked to PD may also lead to phos- 80% of autopsy-examined cases with Lrrk2 parkinsonism pho-tau immunopositive inclusions and apoptosis.46,47 present with typical Lewy body disease consistent with a Results from D melanogaster models show loss of postmortem diagnosis of “definite” PD.31 With the cave- dLRRK (CG5483, the single orthologue of human LRRK1 ats for immunostaining described earlier, it remains un- and LRRK2) may induce degeneration of dopaminergic clear whether Lrrk2 protein is a constituent of Lewy bod- neurons with a consequent locomotor deficit.51 How- ies.28 Intriguingly, some carriers reveal pathological changes ever, the findings are controversial because a kinase- reminiscent of other neurodegenerative disorders. These null dLRRK has been reported to have negligible effects include tau-positive neurofibrillary tangles reminiscent of on the development, life span, or survival of dopamin- argyrophilic grains disease32,33 and pure nigral degenera- ergic neurons.52 Similarly, overexpression of human wild- tion and gliosis without Lewy body pathology but with mul- type LRRK2 complementary DNA (cDNA)and p.G2019S tiple ubiquitin and TDP-43 immunoreactive cytoplasmic mutant proteins in flies, using a panneuronal driver, have and nuclear inclusions.34 “Pleomorphic” pathology can oc- been reported to result in the selective loss of dopamin- cur among Lrrk2 carriers with the same pathogenic mu- ergic neurons and a locomotion deficit.53 However, in tation and even within the same family.8 Hence, Lrrk2 other models of transgenic cDNA overexpression, or with has been dubbed the “Rosetta stone” of parkinsonism, the knock in of equivalent human mutations in the en- perhaps providing a common link between these neuro- dogenous gene, there have been no pathologic effects.51 pathologies. The reason for these disparities is unclear. Most recently, dLRRK was shown to regulate dopamine neuro- FINDINGS ON LRRK2 FUNCTION nal function and maintenance; aged dLRRK-null flies were found to have normal dopaminergic neurons, albeit with Several biochemical studies have shown kinase activity for elevated brain dopamine levels, and wild-type trans- Lrrk2 wild-type protein and a 2- to 10-fold increase of in- genic expression had no effect, whereas mutant overex- tramolecular and intermolecular phosphorylation for the pression demonstrated relatively specific dopaminergic p.G2019S mutant.35 Whether enhanced kinase activity in neuronal toxicity.42 vivo represents a characteristic feature shared by all patho- In C elegans, the nematode worm, LRK-1 localizes to genic Lrrk2 variants remains controversial. Regulation of the Golgi and determines the polarized sorting of syn- Lrrk2 kinase activity is complex, requiring intermolecu- aptic vesicle proteins to axons by excluding them from lar and perhaps intramolecular phosphorylation, and in vitro the dendrite-specific transport machinery.54 Much of the several groups have shown Lrrk2 GTP binding and GT- biology cited on WormBase preceded the discovery of Pase activity has a modifying effect.29,36-38 The Roc-COR do- pathologic LRRK2 mutations (http://www.wormbase

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 .org/). LRK-1–null and knock-down worms have an ex- ing of partner proteins might lead to a dominant nega- perimentally useful chemosensory deficit. Reduced LRK-1 tive effect and result in a similar phenotype. Although expression also appears to make worms more suscep- the p.G2019S mutation may increase kinase activity, it tible to rotenone-induced oxidative stress, although over- may drastically modify its specificity with very different expression of wild-type and mutant Lrrk2 appears to con- consequences for the phosphorylation of a genuine sub- fer neuroprotection.55 Most recently, in C elegans,a strate(s). dominant mutation in Lrk-1 and loss of PINK-1 (PARK6) Alternatively, the discrepancy among kinase activi- have been shown to act antagonistically in stress re- ties of different Lrrk2 mutations may simply reflect a limi- sponse and neurite outgrowth.49 tation of in vitro enzymatic activity assays. Recombi- While the concept of Lrrk2 kinase activity as a key nant Lrrk2 protein might not be in the correct physiologic player in dopaminergic function and parkinsonism has context or there may be a shortage of cofactors neces- been reasonably well established in man, the majority of sary for activation and efficient phosphorylation. Bio- phenotypes described in model organisms have yet to be chemically, it has been shown that the Roc domain can validated in vertebrate models under more physiologi- act as an intrinsic regulator of Lrrk2 kinase activity and cal conditions.56 Several overexpression, bacterial artifi- potentially Lrrk2 must adopt a dimeric conforma- cial chromosome transgenic, murine knockout, and tion.15,70 A model is conceivable where efficient phos- knock-in mouse lines have been developed but publica- phorylation of heterologous Lrrk2 substrates requires a tions to date have focused on their biochemical utility high-molecular-weight Lrrk2 complex, first activated by to study Lrrk2 and its protein interactions.29,56,57 Four in- GTP binding and intramolecular and intermolecular au- dependent mouse models of LRRK2 have recently been tophosphorylation.70,71 Pathologic activation of a Lrrk2 published, 2 based on human or murine LRRK2 bacte- complex via a mutation is consistent with the finding that rial artificial chromosome integration58,59; 1 based on hu- patients with heterozygous or homozygous p.G2019S mu- man cDNA overexpression in an ␣-synuclein overex- tations do not differ in the severity of symptoms, age at pression cross60; and 1, a murine knock in.61 Dopaminergic onset, or disease progression.72 release deficits are consistently reported, with profound Lastly, more emphasis might be placed on Lrrk2’s Ras neuropathology in human bacterial artificial chromo- GTPase activity as a binary switch, cycling between GTP- some and cDNA animals. Which phenotypes will prove bound and GDP-bound forms.12 Monomeric GTPases are philologically insightful in human disease remain to be typically regulated by GTPase-activating proteins and gua- elucidated. nine nucleotide exchange factors, but Lrrk2’s GTPase may A better understanding of Lrrk2’s physiological func- also be regulated through the COR-MAPK domain. Re- tion is required to elucidate Lrrk2’s signaling pathways. lated Ras, Rho, and Rab family members activate mul- Alterations in MAPK signaling have previously been as- tiple effector-mediated signaling pathways and are in- sociated with parkinsonism and PD62,63 and the discov- volved in many biological functions, including gene ery of Lrrk2’s downstream effector kinases is likely to iden- expression, cytoskeletal rearrangement, vesicle traffick- tify additional targets for future therapeutic interventions. ing, cellular proliferation, and oncogenesis. Identifying While more effort is needed, preliminary steps have been Lrrk2’s signaling network mediated by the Roc-COR- undertaken to identify pathways central to Lrrk2 biol- MAPK domains, comprehending its regulation and func- ogy. These include a screen for alterations in the phos- tional consequences, may prove as complicated. phorylation level of MAPK signaling cascades in human The hypothesis that Lrrk2 might function as a mul- subjects,63 microarray expression studies in a Lrrk2 knock- tisubunit complex underlines the need for physiologic ani- down model,64 and identification of Lrrk2 protein inter- mal models; simple overexpression of partial or full- actions,65-68 as well as Lrrk2 kinase inhibitors.35 length wild-type or mutant Lrrk2 under control of a heterologous promoter may not be stoichiometric. Pre- TOWARD A PARSIMONIOUS MOLECULAR serving the Lrrk2 multisubunit complex may be required MODEL OF LRRK2 ACTIVITY for interaction studies and Roc-COR-MAPK assays, although methodologically more challenging. More in- Converging genetic and functional approaches will help sight into Lrrk2 function might be achieved with a vari- elucidate the mechanisms leading to LRRK2-associated ety of knockout and knock-in mutations (including kinase parkinsonism. A central problem is how different patho- and/or GTPase dead); LRRK2 bacterial artificial chromo- genic mutations in Lrrk2, within its many domains (Roc, some transgenics and constitutive and inducible comple- COR, MAPK, and WD40), may be reconciled with 1 phe- mentary DNA expression may be less optimal. notype. Wild-type protein may not normally be an active kinase, although p.G2019S may confer enzymatic ac- CONCLUSIONS tivity in vitro. I2020T adjacent to p.G2019S appears to have lower activity (in most assays) than wild-type pro- Pathogenic Lrrk2 mutants p.R1441C/G/H (Roc), tein but clearly leads to the same disease. Not all pro- p.Y1699C (COR), p.I2012T, p.G2019S, and p.I2020T teins that possess a kinase domain defined by their amino (MAPK) and risk factors p.R1628P (COR) and p.G2385R acid sequence serve to phosphorylate substrates.69 The (WD40) affect the formation and activity of Lrrk2 in dif- presence of several protein-protein interaction domains ferent and specific ways. The risk of disease conferred at the N and C terminal ends suggests Lrrk2 may pri- by Lrrk2 p.G2019S is almost 10-fold greater than con- marily act as a regulatory scaffolding protein. In such a ferred by p.G2385R.18,23 Nevertheless, all LRRK2 muta- model, different mutations that impair adequate bind- tions ultimately lead to the same phenotype and prob-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 ably via the same pathogenic mechanism, whereby 1 lication number WO 2006/045392 A2; international pub- mutant Lrrk2 molecule is sufficient to change the prop- lication number WO 2006/068492 A1; international pub- erties of the entire complex, leading to a dominant effect. lication number US-2008-0009454-A1; and Norwegian The frequency of pathogenic LRRK2 mutations among patent 323175); has received royalties from the licens- patients with PD highlights the importance of a genetic ing of these technologies of greater than $10 000, the US predisposition in this seemingly sporadic neurodegen- federal threshold for significant financial interest; and has erative disorder. Nevertheless, PD should still be con- received salary and royalty payment from Lundbeck Phar- sidered a multifactorial syndrome influenced by a vari- maceuticals. ety of genetic, environmental, and stochastic factors, for which age remains a major determinant. Disease risk may have been most precisely estimated for Lrrk2 p.G2019S REFERENCES but remains a probability rather than a certainty. Pen- etrance is also variable; indeed, some very elderly Lrrk2 1. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. p.G2019S carriers appear to have escaped disease.73 Thus, 2006;5(6):525-535. 2. Kasten M, Chade A, Tanner CM. Epidemiology of Parkinson’s disease. Handb widespread genetic screening for LRRK2 mutations in Clin Neurol. 2007;83:129-151. asymptomatic subjects is not warranted. In contrast, ge- 3. Wirdefeldt K, Gatz M, Bakaysa SL, et al. 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The Parkinson disease gene LRRK2: evolutionary and structural insights. nity to successfully diagnose and develop novel molecu- Mol Biol Evol. 2006;23(12):2423-2433. 17. Taylor JP, Hulihan MM, Kachergus JM, et al. Leucine-rich repeat kinase 1: a para- lar therapeutics for Lrrk2 parkinsonism and PD has never log of LRRK2 and a candidate gene for Parkinson’s disease. Neurogenetics. 2007; been greater. 8(2):95-102. 18. Hulihan MM, Ishihara-Paul L, Kachergus J, et al. LRRK2 Gly2019Ser pen- Accepted for Publication: March 8, 2009. etrance in Arab-Berber patients from Tunisia: a case-control genetic study. Lan- cet Neurol. 2008;7(7):591-594. Correspondence: Matthew J. Farrer, PhD, Morris K. Udall 19. Healy DG, Falchi M, O’Sullivan SS, et al; International LRRK2 Consortium. Phe- Parkinson’s Disease Research Center of Excellence, Labo- notype, genotype, and worldwide genetic penetrance of LRRK2-associated Par- ratories of Neurogenetics, Birdsall Bldg, Mayo Clinic, De- kinson’s disease: a case-control study. Lancet Neurol. 2008;7(7):583-590. partment of Neuroscience, 4500 San Pablo Rd, Jackson- 20. Zabetian CP, Hutter CM, Yearout D, et al. LRRK2 G2019S in families with Par- ville, FL 32224 ([email protected]). kinson disease who originated from Europe and the Middle East: evidence of two distinct founding events beginning two millennia ago. Am J Hum Genet. 2006; Author Contributions: Study concept and design: Däch- 79(4):752-758. sel and Farrer. Drafting of the manuscript: Dächsel. Ob- 21. Orr-Urtreger A, Shifrin C, Rozovski U, et al. The LRRK2 G2019S mutation in Ash- tained funding: Farrer. kenazi Jews with Parkinson disease: is there a gender effect? Neurology. 2007; Financial Disclosure: Dr Farrer has filed US and Euro- 69(16):1595-1602. 22. Ozelius LJ, Senthil G, Saunders-Pullman R, et al. LRRK2 G2019S as a cause of pean patents for the identification of LRKK2 and patho- Parkinson’s disease in Ashkenazi Jews. N Engl J Med. 2006;354(4):424-425. genic mutations including 6055GϾA (G2019S) linked 23. Farrer MJ, Stone JT, Lin CH, et al. Lrrk2 G2385R is an ancestral risk factor for to autosomal dominant parkinsonism (international pub- Parkinson’s disease in Asia. Parkinsonism Relat Disord. 2007;13(2):89-92.

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 24. Ross OA, Wu YR, Lee MC, et al. Analysis of Lrrk2 R1628P as a risk factor for Caenorhabditis elegans LRK-1 and PINK-1 act antagonistically in stress re- Parkinson’s disease. Ann Neurol. 2008;64(1):88-92. sponse and neurite outgrowth. J Biol Chem. 2009;284(24):16482-16491. 25. Tan EK. Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in 50. Parisiadou L, Xie C, Cho HJ, et al. Phosphorylation of ezrin/radixin/moesin pro- Parkinson’s disease. Ann Acad Med Singapore. 2006;35(11):840-842. teins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal 26. Funayama M, Li Y, Tomiyama H, et al. Leucine-rich repeat kinase 2 G2385R vari- morphogenesis. J Neurosci. 2009;29(44):13971-13980. ant is a risk factor for Parkinson disease in Asian population. Neuroreport. 2007; 51. Lee SB, Kim W, Lee S, Chung J. 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