Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent identification of a common genetic variant (LRRK2 G2385R) which is associated with a two-fold increased risk of sporadic Parkinson's Disease (PD) in two independent Chinese populations in Singapore and Taiwan has generated considerable excitement. Thus far, this variant appears specific for the Asian population, emphasising further that ethnic-specific effects should be considered in genetic association studies. Cautious optimism is advised as we await more scientific studies and clarification if this risk variant is specific to ethnic Chinese race. Our in-vitro studies suggest the Gly2385Arg variant is biologically relevant and it might act through pro-apoptotic mechanisms, especially under cellular stresses. This may provide a partial explanation why some carriers develop the disease while others do not. The presence of other epigenetic factors, gene-gene and gene-environmental interaction could modulate the phenotype expression. Further validation of these findings would be needed to confirm this variant as the single most important common genetic risk factor in ethnic Chinese and/or Asian PD patients. The identification of the LRRK2 Gly2385Arg variant could potentially facilitate the development of clinical, bioimaging, genetic and biological biomarkers, useful in the monitoring and neuroprotective therapy in asymptomatic individuals.
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PMID:Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease. 1716 Feb 3

We report the results of a family-based study of LRRK2 G2019S penetrance in Parkinson disease. We studied 19 families identified through the analysis of unrelated consecutive patients. The cumulative incidence of the disease was 15% at 60 years, 21% at 70 years, and 32% at 80 years. This study provides accurate estimates of G2019S penetrance by minimizing the selection bias.
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PMID:Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease. 1721 92

An increasing number of nonsynonymous LRRK2 variants are being reported as putative pathogenic mutations. We identified one large kindred harboring the Lrrk2 R1514Q substitution; however, the variant did not segregate fully with disease. Combined analyses of three case-control series demonstrate that the R1514Q substitution is not associated with increased risk of disease (OR: 1.3; 95% CI: 0.6-2.8; P = 0.45). These findings highlight the importance of using family-based studies and multiple population screenings when examining the association of these polymorphic LRRK2 gene variants with Parkinson's disease.
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PMID:Pathogenicity of the Lrrk2 R1514Q substitution in Parkinson's disease. 1721 39

Mutations in SNCA and LRRK2 genes, encoding alpha-synuclein and leucine-rich repeat kinase 2, respectively, cause autosomal dominant Parkinson's disease (AdPD). The LRRK2 G2019S (c.6055G > A) and R1441G (c.4321C > G) mutations have also been identified in sporadic PD (sPD). We studied 55 unrelated patients with AdPD, 235 patients with sPD, and 235 healthy age- and gender-matched controls all of Greek origin. Patients with AdPD were screened for SNCA and LRRK2 mutations by direct sequencing. SNCA gene dosage analysis was also performed for AdPD using quantitative duplex polymerase chain reaction of genomic DNA. In addition, we investigated the frequency of the LRRK2 G2019S mutation in sPD. We found no missense mutations or multiplications in the SNCA gene. Here we report two novel variants, A211V (c.632C > T) and K544E (c.1630A > G) in LRRK2 gene in two patients with AdPD that was not present in controls. We identified only one patient with sPD (1/235; 0.4%) carrying the G2019S mutation. LRRK2 mutations are present in AdPD and sPD patients of Greek origin.
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PMID:Screening for SNCA and LRRK2 mutations in Greek sporadic and autosomal dominant Parkinson's disease: identification of two novel LRRK2 variants. 1722 6

Leucine-rich repeat kinase 1 gene (LRRK1) on chromosome 15q26.3 is a paralog of LRRK2 in which multiple substitutions were recently linked to Parkinson's disease. We have examined the exon-intron structure of the gene and the expressed mRNA sequence in brain. LRRK1 sequencing analysis in 95 probands from families with autosomal dominant Parkinson's disease identified 23 variants, 14 of which are novel, with four resulting in non-synonymous amino acid substitutions. These four substitutions are rare and do not clearly segregate with disease within our families or associate with sporadic Parkinson's disease in a US case-control series. Subsequent sequencing of exon 26 encoding the kinase activation segment in an additional 360 probands identified one further synonymous variant, suggesting that LRRK1 variants are not a frequent cause of Parkinson's disease. The relative absence of substitutions within LRRK1 highlights a greater conservation of sequence than observed for LRRK2. Comparison of evolutionary interspecies sequences of LRRK1 and LRRK2 suggests they diverged from a common founder gene.
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PMID:Leucine-rich repeat kinase 1: a paralog of LRRK2 and a candidate gene for Parkinson's disease. 1722 81

Several pathogenic mutations in the LRRK2 gene have been implicated in familial and sporadic cases of Parkinson's disease (PD). We screened 103 sporadic French PD patients for the presence of the LRRK2 R1441G and G2019S mutations. The R1441G mutation was absent in our PD sporadic cases, but the G2019S mutation was present in 2 of them (1.9%). Clinical features in our 2 patients were not different from classic PD. One of our patients was of Berberian (North Africa) origin. Our 2 patients displayed genetic profiles consistent with the same ancestral haplotype as previously reported for carriers of the LRRK2 G2019S mutation.
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PMID:Genetic screening for two LRRK2 mutations in French patients with idiopathic Parkinson's disease. 1725 37

The discovery of LRRK2 gene mutations in late-onset Parkinson's disease (PD) has irrevocably established the role of genetics in the etiology of PD. The LRRK1 gene is the single homolog of LRRK2. A high degree of homology exists between LRRK1 and LRRK2, indicative of shared functions and/or pathways. One study has examined LRRK1 in familial parkinsonism by complete sequencing of the gene, reporting 4 novel non-synonymous coding variants within the LRRK1 gene. One of these variants (ss65713826) was identified in a Norwegian proband. We investigated whether five common polymorphisms or these recently identified coding changes within LRRK1 are associated with PD in the Norwegian population. Two rare coding variants ss65713826 and ss65713830 were more frequent in patients than controls. However, their identification in healthy controls and lack of co-segregation with disease suggests they may represent benign polymorphisms.
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PMID:Variants in the LRRK1 gene and susceptibility to Parkinson's disease in Norway. 1732 17

Parkinson disease (PD; Parkinson's) is the second most common neurodegenerative disease, characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies. Increasing evidence suggests that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system (UPS) dysfunction may represent the principal molecular pathways that commonly underlie the pathogenesis. The relative role of genetic and environmental factors has been the focus of research and debate. The recent discovery of a number of disease-causing genes (SNCA, Parkin/PARK2, UCHL1, PINK1, DJ1/PARK7, and LRRK2) in familial and sporadic forms of PD has provided considerable insights into the pathophysiology of this complex disorder. The frequency of these gene mutations may vary according to ethnicity and to the specific gene. A gene dosage effect is observed in some cases, and the phenotype of some of the mutation carriers closely resembles typical PD. Penetrance of some of the recurrent mutations is incomplete and may vary with age. Further research to unravel the etiopathology could identify biochemical or genetic markers for potential neuroprotective trials.
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PMID:Pathogenic mutations in Parkinson disease. 1738 68

Hyperechogenicity of the substantia nigra (SN) has been found to be a typical sign in idiopathic Parkinson's disease (PD), prevalent in more than 90% of affected individuals. To see whether SN hyperechogenicity is also characteristic for monogenetically caused PD, we investigated PD patients with alpha-synuclein, LRRK2, parkin, PINK1 and DJ-1 mutations by transcranial sonography (TCS). In all these patients the area of SN echogenicity was significantly larger than in healthy controls, but smaller, than in idiopathic PD. As SN hyperechogenicity could be related to an increased iron content of the SN, these findings suggest that iron may play a less significant role in the pathogenesis of monogenetically caused compared to idiopathic PD.
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PMID:Transcranial ultrasound in different monogenetic subtypes of Parkinson's disease. 1741 11

Mutations in the LRRK2 (leucine-rich repeat kinase-2) gene cause late-onset PD (Parkinson's disease). LRRK2 contains leucine-rich repeats, a GTPase domain, a COR [C-terminal of Roc (Ras of complex)] domain, a kinase and a WD40 (Trp-Asp 40) motif. Little is known about how LRRK2 is regulated, what its physiological substrates are or how mutations affect LRRK2 function. Thus far LRRK2 activity has only been assessed by autophosphorylation and phosphorylation of MBP (myelin basic protein), which is catalysed rather slowly. We undertook a KESTREL (kinase substrate tracking and elucidation) screen in rat brain extracts to identify proteins that were phosphorylated by an activated PD mutant of LRRK2 (G2019S). This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by LRRK2, at Thr558, a previously identified in-vivo-phosphorylation site that regulates the ability of moesin to bind actin. LRRK2 also phosphorylated ezrin and radixin, which are related to moesin, at the residue equivalent to Thr558, as well as a peptide (LRRKtide: RLGRDKYKTLRQIRQ) encompassing Thr558. We exploited these findings to determine how nine previously reported PD mutations of LRRK2 affected kinase activity. Only one of the mutations analysed, namely G2019S, stimulated kinase activity. Four mutations inhibited LRRK2 kinase activity (R1941H, I2012T, I2020T and G2385R), whereas the remainder (R1441C, R1441G, Y1699C and T2356I) did not influence activity. Therefore the manner in which LRRK2 mutations induce PD is more complex than previously imagined and is not only caused by an increase in LRRK2 kinase activity. Finally, we show that the minimum catalytically active fragment of LRRK2 requires an intact GTPase, COR and kinase domain, as well as a WD40 motif and a C-terminal tail. The results of the present study suggest that moesin, ezrin and radixin may be LRRK2 substrates, findings that have been exploited to develop the first robust quantitative assay to measure LRRK2 kinase activity.
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PMID:LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. 1744 91


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