Population‐specific frequencies for <i>LRRK2</i> susceptibility variants in the genetic epidemiology of Parkinson's disease (GEO‐PD) consortium

Heckman, Michael G.; Soto‐Ortolaza, Alexandra I.; Aasly, Jan; Abahuni, Nadine; Annesi, Grazia; Bacon, Justin A.; Bardien, Soraya; Bozi, Maria; Brice, Alexis; Brighina, Laura; Carr, Jonathan; Chartier-Harlin, Marie-Christine; Dardiotis, Efthimios; Dickson, Dennis W.; Diehl, Nancy N.; Elbaz, Alexis; Ferrarese, Carlo; Fiske, Brian; Gibson, J. M.; Gibson, Rachel; Hadjigeorgiou, Georgios M.; Hattori, Nobutaka; Ioannidis, John P. A.; Boczarska-Jedynak, Magdalena; Jasińska-Myga, Barbara; Jeon, Beom S.; Kim, Yun Joong; Klein, Christine; Krüger, Rejko; Kyratzi, Elli; Lesage, Suzanne; Lin, Chin‐Hsien; Lynch, Timothy; Maraganore, Demetrius M.; Mellick, George D.; Mutez, Eugénie; Nilsson, Christer; Opala, Grzegorz; Park, Sung Sup; Petrucci, Simona; Puschmann, Andreas; Quattrone, Aldo; Sharma, Manu; Silburn, Peter A.; Sohn, Young H.; Stefanis, Leonidas; Tadić, Vera; Theuns, Jessie; Tomiyama, Hiroyuki; Uitti, Ryan J.; Valente, Enza Maria; Broeckhoven, Christine Van; Loo, Simone van de; Vassilatis, Demetrios K.; Vilariño‐Güell, Carles; White, Linda R.; Wirdefeldt, Karin; Wszołek, Zbigniew K.; Wu, Ruey‐Meei; Hentati, Fayçal; Farrer, Matthew J.; Ross, Owen A.

doi:10.1002/mds.25600

Cited by 33 publications

(36 citation statements)

References 15 publications

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“…Additional variants in the Roc domain such as I1371V are found in individual PD cases but have not yet been confirmed by segregation analyses in families [8, 26]. The protective R1398H variant is associated with PD in certain populations suggesting that variation within the GTPase domain may also be beneficial [27–29]. The familial Y1699C mutation, identified in German-Canadian and UK families, is the only known disease-causing variant located within the COR domain (residues 1510–1850) [4, 30].…”

Section: Gtpase Domain and Activitymentioning

confidence: 99%

Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity

Nguyen

Moore

2017

Advances in Neurobiology

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of Parkinson’s disease (PD) with late-onset and autosomal-dominant inheritance. LRRK2 belongs to the ROCO superfamily of proteins, characterized by a Ras-of-complex (Roc) GTPase domain in tandem with a C-terminal-of-Roc (COR) domain. LRRK2 also contains a protein kinase domain adjacent to the Roc-COR tandem domain in addition to multiple repeat domains. Disease-causing familial mutations cluster within the Roc-COR tandem and kinase domains of LRRK2, where they act to either impair GTPase activity or enhance kinase activity. Familial LRRK2 mutations share in common the capacity to induce neuronal toxicity in cultured cells. While the contribution of the frequent G2019S mutation, located within the kinase domain, to kinase activity and neurotoxicity has been extensively investigated, the contribution of GTPase activity has received less attention. The GTPase domain has been shown to play an important role in regulating kinase activity, in dimerization, and in mediating the neurotoxic effects of LRRK2. Accordingly, the GTPase domain has emerged as a potential therapeutic target for inhibiting the pathogenic effects of LRRK2 mutations. Many important mechanisms remain to be elucidated, including how the GTPase cycle of LRRK2 is regulated, whether GTPase effectors exist for LRRK2, and how GTPase activity contributes to the overall functional output of LRRK2. In this review, we discuss the importance of the GTPase domain for LRRK2-linked PD focusing in particular on its regulation, function, and contribution to neurotoxic mechanisms.

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Section: Gtpase Domain and Activitymentioning

confidence: 99%

Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity

Nguyen

Moore

2017

Advances in Neurobiology

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“…Among the identified LRRK2 mutations, at least seven missense mutations (N1437H, R1441C, R1441G, R1441H, Y1699C, G2019S, and I2020T) are considered to be truly pathogenic based upon segregation with disease in LRRK2 -linked families (Figure 1) [4]. In addition, many LRRK2-coding variants are associated with PD risk, including G2385R and R1628P, which confer increased risk in Asian populations, whereas a N551K-R1398H haplotype may confer a protective effective [8,9]. Genome-wide association studies have also identified common variants (or single nucleotide polymorphisms) at the LRRK2 locus that increase risk for idiopathic PD, although it is not yet clear how these SNPs that are enriched in gene regulatory regions influence LRRK2 expression in different tissues [5,10].…”

Section: Leucine-rich Repeat Kinase 2 and Parkinson’s Diseasementioning

confidence: 99%

Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity and protein aggregation

Islam

Moore

2017

Biochemical Society Transactions

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson’s disease (PD) with autosomal dominant inheritance. Accordingly, LRRK2 has emerged as a promising therapeutic target for disease modification in PD. Since the first discovery of LRRK2 mutations some 12 years ago, LRRK2 has been the subject of intense investigation. It has been established that LRRK2 can function as a protein kinase, with many putative substrates identified, and can also function as a GTPase that may serve in part to regulate kinase activity. Familial mutations influence both of these enzymatic activities, suggesting that they may be important for the development of PD. Many LRRK2 models have been established to understand the pathogenic effects and mechanisms of familial mutations. Here, we provide a focused discussion of the evidence supporting a role for kinase and GTPase activity in mediating the pathogenic effects of familial LRRK2 mutations in different model systems, with an emphasis on rodent models of PD. We also critically discuss the contribution and relevance of protein aggregation, namely of α-synuclein and tau-proteins, which are known to form aggregates in PD brains harboring LRRK2 mutations, to neurodegeneration in LRRK2 rodent models. We aim to provide a clear and unbiased review of some of the key mechanisms that are important for LRRK2-dependent neurodegeneration in PD.

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“…It has been shown that the p.1398H variant has reduced kinase activity in comparison to the wild type p.R1398 (Tan et al 2010). Given these data, the p.R1398H (rs7133914) substitution, which occurs with a MAF of approximately 7% in Caucasians and 10% in Asians (Heckman et al, in press; Tan et al, 2010), is the most likely functional variant on the haplotype. The protective effect of p.R1398H appears strongest in Asians, where consistent odds ratios of 0.75 and 0.73 have been observed in studies by Tan et al (2010) and Ross et al (2011), with a similar odds ratio of 0.79 observed in a smaller study by Chen et al (2011).…”

Section: Introductionmentioning

confidence: 99%

The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

Heckman

Elbaz

Soto‐Ortolaza

et al. 2014

Neurobiology of Aging

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The best validated susceptibility variants for Parkinson’s disease (PD) are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined four SNCA variants (rs181489, rs356219, rs11931074, rs2583988), the MAPT H1-haplotype defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (N=10,322) and Asian (N=2,289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all P≥0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with PD is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

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Population‐specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinson's disease (GEO‐PD) consortium

Cited by 33 publications

References 15 publications

Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity

Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity

Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity and protein aggregation

The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

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