Parkinson's Disease: The LRRK2-G2019S mutation: opening a novel era in Parkinson's disease genetics

Bonifati, Vincenzo

doi:10.1038/sj.ejhg.5201695

Cited by 56 publications

(29 citation statements)

References 18 publications

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“…The G2019S mutation, located in the MAPKKK domain, is by far the most common and was identified by several groups as a cause of both familial and sporadic PD. The frequency of this mutation in PD varies greatly across populations (Bonifati 2006). Studies from large series in the United States estimated a mutation frequency of ~3% in familial and ~1% in sporadic cases (Clark et al 2006; Kay et al 2006).…”

Section: Prevalence and Pathological Features Of Lrrk2 Disease-associmentioning

confidence: 99%

Leucine‐rich repeat kinase 2 (LRRK2): A key player in the pathogenesis of Parkinson's disease

Gandhi

Chen

Wilson-Delfosse

2008

J of Neuroscience Research

112

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Parkinson’s disease (PD) is the most common neurodegenerative movement disorder with a prevalence of more than 1% after the age of 65 years. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) have recently been linked to autosomal dominant, late-onset PD that is clinically indistinguishable from typical, idiopathic disease. LRRK2 is a multi-domain protein containing several protein interaction motifs as well as dual enzymatic domains of GTPase and protein kinase activities. Disease-associated mutations are found throughout the multi-domain structure of the protein. LRRK2, however, is unique among the PD-causing genes because a missense mutation, G2019S, is a frequent determinant of not only familial, but also of sporadic PD. Thus, LRRK2 has emerged as a promising therapeutic target for combating PD. This article reviews the current state of knowledge regarding the domain structure, amino acid substitutions, and potential functional roles of LRRK2.

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Section: Prevalence and Pathological Features Of Lrrk2 Disease-associmentioning

confidence: 99%

Leucine‐rich repeat kinase 2 (LRRK2): A key player in the pathogenesis of Parkinson's disease

Gandhi

Chen

Wilson-Delfosse

2008

J of Neuroscience Research

112

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“…Specific mutations in leucine-rich repeat kinase (LRRK2, PARK8) gene have been identified as responsible for autosomal dominant familial PD (6,7), and most of the LRRK2-linked families show a clinical and in vivo neurochemical phenotype that is indistinguishable from idiopathic PD (8). Clinicogenetic studies from several independent groups have evaluated the frequency of LRRK2 mutations in several different populations and such mutations have been found not only in the 5-6% of familial PD but also in 1-2% of idiopathic PD (9,10).…”

Section: Introductionmentioning

confidence: 99%

Apoptotic mechanisms in mutant LRRK2-mediated cell death

Iaccarino¹,

Crosio²,

Vitale³

et al. 2007

Human Molecular Genetics

176

153

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“…LRRK2 is a complex 286-kDa protein that consists of multiple domains, including (in order, from the amino to carboxyl terminus) armadillo, ankyrin, and the namesake leucine-rich repeats (LRRs), followed by an ROC (Ras of complex proteins) GTPase domain, a COR (C-terminal of ROC) dimerization domain, a kinase domain, and a predicted C-terminal WD40 repeat domain (4-6). Several single-nucleotide alterations have been identified in LRRK2, but only five missense mutations within the ROC, COR, and kinase domains clearly segregate with PD in large family studies (7,8). It has recently been shown that the WD40 domain is required to stabilize the LRRK2 dimer and to execute LRRK2-associated kinase activity as well as neurotoxicity (9, 10), but the role of this domain within LRRK2 physiological and pathological function has not yet been completely defined.…”

mentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 Binds to Neuronal Vesicles through Protein Interactions Mediated by Its C-Terminal WD40 Domain

Piccoli

Onofri

Cirnaru

et al. 2014

Molecular and Cellular Biology

108

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jMutations in the leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains, including predicted C-terminal WD40 repeats. In this study, we analyzed functional and molecular features conferred by the WD40 domain. Electron microscopic analysis of the purified LRRK2 C-terminal domain revealed doughnut-shaped particles, providing experimental evidence for its WD40 fold. We demonstrate that LRRK2 WD40 binds and sequesters synaptic vesicles via interaction with vesicle-associated proteins. In fact, a domain-based pulldown approach combined with mass spectrometric analysis identified LRRK2 as being part of a highly specific protein network involved in synaptic vesicle trafficking. In addition, we found that a C-terminal sequence variant associated with an increased risk of developing PD, G2385R, correlates with a reduced binding affinity of LRRK2 WD40 to synaptic vesicles. Our data demonstrate a critical role of the WD40 domain within LRRK2 function. Parkinson's disease (PD) is the second most common age-related neurodegenerative disease and is clinically characterized by movement impairments, bradykinesia, rigidity, and resting tremor and pathologically by the progressive loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (1, 2). Although the majority of cases are sporadic, mutations in the leucine-rich repeat kinase 2 (LRRK2) gene (PARK8; Online Mendelian Inheritance in Man [OMIM] accession number 609007) had been unequivocally linked to late-onset autosomal dominant PD. LRRK2 mutations account for up to 13% of familial PD cases compatible with dominant inheritance and are also found in 1 to 2% of sporadic PD patients (62-64). LRRK2 is a complex 286-kDa protein that consists of multiple domains, including (in order, from the amino to carboxyl terminus) armadillo, ankyrin, and the namesake leucine-rich repeats (LRRs), followed by an ROC (Ras of complex proteins) GTPase domain, a COR (C-terminal of ROC) dimerization domain, a kinase domain, and a predicted C-terminal WD40 repeat domain (4-6). Several single-nucleotide alterations have been identified in LRRK2, but only five missense mutations within the ROC, COR, and kinase domains clearly segregate with PD in large family studies (7,8). It has recently been shown that the WD40 domain is required to stabilize the LRRK2 dimer and to execute LRRK2-associated kinase activity as well as neurotoxicity (9, 10), but the role of this domain within LRRK2 physiological and pathological function has not yet been completely defined. The beta-propellerforming WD40 domains are among the 10 most abundant domain types across eukaryotic proteomes (11) and constitute platforms where multiprotein complexes assemble reversibly (12). Here, we systematically analyzed the protein-protein interactions conferred by the LRRK2 WD40 domain. The nature of the LRRK2 WD40 interactors and the finding that the LRRK2 WD40 domain is able to bind to synaptic...

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Parkinson's Disease: The LRRK2-G2019S mutation: opening a novel era in Parkinson's disease genetics

Cited by 56 publications

References 18 publications

Leucine‐rich repeat kinase 2 (LRRK2): A key player in the pathogenesis of Parkinson's disease

Leucine‐rich repeat kinase 2 (LRRK2): A key player in the pathogenesis of Parkinson's disease

Apoptotic mechanisms in mutant LRRK2-mediated cell death

Leucine-Rich Repeat Kinase 2 Binds to Neuronal Vesicles through Protein Interactions Mediated by Its C-Terminal WD40 Domain

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