Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease

Ross, Owen A.; Wu, Yih‐Ru; Lee, Mei‐Ching; Funayama, Manabu; Chen, Meng‐Ling; Soto, Alexandra I.; Mata, Ignacio; Lee‐Chen, Guey‐Jen; Chen, Chiung Mei; Tang, Michelle; Zhao, Yongxiang; Hattori, Nobutaka; Farrer, Matthew J.; Tan, Eng‐King; Wu, Ruey‐Meei

doi:10.1002/ana.21405

Cited by 181 publications

(169 citation statements)

References 14 publications

(28 reference statements)

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“…18 for a detailed review on LRRK2 genetics). Among these, the coding variants G2385R in the WD40 domain and R1628P in the COR domain act as common PD risk factors among Asian populations 44, 45, 46. The G2385R variant essentially doubles the lifetime risk of getting PD 47.…”

Section: Lrrk2 Genetics Protein Domain Structure; Kinase and Gtpase mentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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Section: Lrrk2 Genetics Protein Domain Structure; Kinase and Gtpase mentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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“…Two variants in LRRK2 that are predominantly found in Asian populations, G2385R [93][94][95][96][97] and R1628P [98][99][100][101], increase the lifetime risk of PD about 2-fold [102]. Molecular modeling predicts that the G2385 residue is located on the outer surface of the WD40 domain towards the C-terminus of LRRK2 [31].…”

Section: Genetic Risk Factors Associated With Parkinson's Diseasementioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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“…1 Although the majority of PD is idiopathic, pathogenic mutations have successfully been identified in some mendelian forms. 2 Many of these mendelian genes have also been investigated in the idiopathic disease, but only SNPs at the SNCA and LRRK2 loci have shown susceptibility for idiopathic PD (IPD): several SNPs at the SNCA locus have been characterized as risk factors for IPD in different populations, 3 a LRRK2-associated haplotype showed an increased disease risk in the Chinese population, 4 two LRRK2 mutations absent in European ancestry populations are overrepresented in PD in some Asian populations 5,6 and common LRRK2 variation may also contribute to the risk for IPD in the North American population. 7 Similarly, the frequency and distribution of GBA mutations in PD vary within populations, being more prevalent among the Ashkenazi Jewish population and rare among Asians.…”

Section: Introductionmentioning

confidence: 99%

Genetic variability at the PARK16 locus

Tucci¹,

Nalls

Houlden³

et al. 2010

Eur J Hum Genet

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Parkinson's disease (PD) is a complex neurodegenerative disease which is clinically heterogeneous and pathologically consists of loss of dopaminergic neurons in the substantia nigra and intracytoplasmic neuronal inclusions containing alpha-synuclein aggregations known as Lewy bodies. Although the majority of PD is idiopathic, pathogenic mutations in several mendelian genes have been successfully identified through linkage analyses. To identify susceptibility loci for idiopathic PD, several genome-wide association studies (GWAS) within different populations have recently been conducted in both idiopathic and familial forms of PD. These analyses have confirmed SNCA and MAPT as loci harboring PD susceptibility. In addition, the GWAS identified several other genetic loci suggestively associated with the risk of PD; among these, only one was replicated by two different studies of European and Asian ancestries. Hence, we investigated this novel locus known as PARK16 for coding mutations in a large series of idiopathic pathologically proven PD cases, and also conducted an association study in a case-control cohort from the United Kingdom. An association between a novel RAB7L1 mutation, c.379-12insT, and disease (P-value¼0.0325) was identified. Two novel coding variants present only in the PD cohort were also identified within the RAB7L1 (p.K157R) and SLC41A1 (p.A350V) genes. No copy number variation analyses have yet been performed within this recently identified locus. We concluded that, although both coding variants and risk alleles within the PARK16 locus seem to be rare, further molecular analyses within the PARK16 locus and within different populations are required in order to examine its biochemical role in the disease process.

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Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease

Cited by 181 publications

References 14 publications

Cellular processes associated with LRRK2 function and dysfunction

Cellular processes associated with LRRK2 function and dysfunction

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Genetic variability at the PARK16 locus

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