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

Human leucine-rich repeat kinase 2 (LRRK2) is a novel kinase belonging to the ROCO protein superfamily (Ras of complex proteins (Roc) with a C-terminal of Roc domain). This large complex protein of 280kDa contains several functional domains including leucine-rich repeats, Ras-related GTPase, mitogen-activated protein kinase kinase kinase (MAPKKK), and WD40 repeats. While definitive functions of LRRK2 have yet to be described, the domain structure of LRRK2 suggests that it plays an important role in the regulation of signal transduction cascades through its dual enzymatic activities of GTPase and MAPKKK. Moreover, mutations in LRRK2 have been found to be thus far the most frequent cause of late-onset familial and idiopathic Parkinson's disease. Further investigations should allow for the elucidation of how pathogenic mutations trigger changes in the structure and function of LRRK2 that lead to aberrant signal transduction and neurodegeneration in Parkinson's disease.
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PMID:Leucine-rich repeat kinase 2: relevance to Parkinson's disease. 1660 Jun 64

The pleomorphic pathology of postmortem LRRK2-positive patients and the frequent association with late-onset Parkinson's disease (LOPD) symptoms suggest that LRRK2 mutations may play a role in Parkinson's Plus disorders and LOPD. Published studies primarily focus on the common G2019S mutation. Analysis of a spectrum of LRRK2 mutations in Parkinson's Plus disorders has yet to be reported. We investigated 14 leucine-rich repeat kinase 2 (LRRK2) mutations in a cohort of Parkinson's Plus disorders and LOPD. A total of 458 patients with progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal ganglionic degeneration (CBGD), atypical Parkinsonism (AP), and LOPD were screened for 14 mutations that span exons 19 to 41 of the LRRK2 gene. Among the LOPD cases, 1 patient was found to harbor the R1441C mutation. He presented with typical features of PD at age of 58 years old and responded well to levodopa. We did not detect any of the 14 mutations in PSP, MSA, CBGD, and AP patients. We highlight the first case of LRRK2 R1441C mutation in late onset sporadic PD of non-European ancestry. Furthermore, extensive mutational screen found LRRK2 mutations to be rare among patients who presented with PSP, MSA, CBGD, and AP.
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PMID:Analysis of 14 LRRK2 mutations in Parkinson's plus syndromes and late-onset Parkinson's disease. 1660 13

Parkinson's disease (PD) is the most common motor neurodegenerative disease. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) have been linked recently with autosomal-dominant parkinsonism that is clinically indistinguishable from typical, idiopathic, late-onset PD. Thus, the protein LRRK2 has emerged as a promising therapeutic target for treatment of PD. LRRK2 is extraordinarily large and complex, with multiple enzymatic and protein-interaction domains, each of which is targeted by pathogenic mutations in familial PD. This review places the PD-associated mutations of LRRK2 in a structural and functional framework, with the ultimate aim of deciphering the molecular basis of LRRK2-associated pathogenesis. This, in turn, should advance our understanding and treatment of familial and idiopathic PD.
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PMID:LRRK2 in Parkinson's disease: protein domains and functional insights. 1661 79

Mutations in leucine-rich repeat kinase 2 gene (LRRK2) have been associated with idiopathic Parkinson's disease (PD), as well as pleomorphic neurodegenerative pathology, including Alzheimer's disease. One specific LRRK2 mutation, G2019S, was reported in 18% of people with PD of Ashkenazi descent, supporting a founder effect in this population. To determine if this mutation is also associated with dementia in the Ashkenazim, we screened 192 elderly Ashkenazi Jewish (AJ) individuals in a longitudinal aging and cognition study, of whom 49 (25.5%) had dementia. Two non-demented individuals harbored the mutation (2/143, 1.4%), but no individuals with dementia. Neither person with the mutation had Parkinson's disease. Therefore, the LRRK2 mutation has a relatively high frequency in the AJ population, is not fully penetrant for parkinsonism in the elderly, and does not appear to be commonly associated with late-onset dementia.
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PMID:Increased frequency of the LRRK2 G2019S mutation in an elderly Ashkenazi Jewish population is not associated with dementia. 1663 1

Pathogenic mutations in the leucine-rich repeat kinase 2 gene (LRRK2; PARK8) have been implicated in autosomal dominant, late-onset parkinsonism. The LRRK2 6055G > A (G2019S) mutation is the most common reported to date, and has been observed in a number of different European populations. So far, only the LRRK2 4321C > G (R1441G) mutation has been identified in the Spanish population. Herein we have assessed the frequency of G2019S in a referral-based series of 225 patients with Parkinson's disease (PD) from the region of Asturias, Northern Spain. The mutant allele was identified in five (2.7%) of the sporadic late-onset patients and was not present in control subjects. All carriers displayed genetic profiles consistent with the same haplotype, as previously reported for Lrrk2 G2019S-positive subjects. None of these patients presented with a family history of parkinsonism at the time of diagnosis. Thus, approximately 5% of sporadic patients with PD from the North of Spain have either Lrrk2 G2019S or R1441G substitutions.
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PMID:LRRK2 mutations are a common cause of Parkinson's disease in Spain. 1664 18

Mutations in LRRK2 (leucine-rich repeat kinase 2) have been associated with autosomal dominant Parkinson's disease (PD) and cluster in several 3' exons of the gene. The majority of mutations have been detected in late-onset cases (age at onset >50 years). We screened 5 of the 51 exons of LRRK2 that previously have been reported to harbor mutations in 98 early-onset and 42 late-onset PD patients. We identified two mutations (c.4321C>T, c.6055G>A) in three early-onset patients. Screening of an additional 220 early-onset PD patients for these mutations revealed another mutation carrier. In conclusion, LRRK2 mutations need to be considered also in early-onset PD.
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PMID:Recurrent LRRK2 (Park8) mutations in early-onset Parkinson's disease. 1675 83

Mutations in two kinases, PTEN induced kinase 1 (PINK1) and leucine-rich repeat kinase 2 (LRRK2), have been shown to segregate with familial forms of Parkinson's disease. Although these two genes are expected to be involved in molecular mechanisms relevant to Parkinson's disease, their precise anatomical localization in mammalian brain is unknown. We have mapped the expression of PINK1 and LRRK2 mRNA in the rat and mouse brain via in situ hybridization histochemistry using riboprobes. We found that both genes are broadly expressed throughout the brain with similar neuroanatomical distribution in mouse compared to rat. PINK1 mRNA abundance was rather uniform throughout the different brain regions with expression in cortex, striatum, thalamus, brainstem and cerebellum. LRRK2, on the other hand, showed strong regional differences in expression levels with highest levels seen in the striatum, cortex and hippocampus. Weak LRRK2 expression was seen in the hypothalamus, olfactory bulb and substantia nigra. We confirmed these distributions for both genes using quantitative RT-PCR and for LRRK2 by western immunoblot. As their broad expression patterns contrast with localized neuropathology in Parkinson's disease, the pathogenicity of clinical mutant forms of PINK1 and LRRK2 may be mediated by nigrostriatal-specific mechanisms.
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PMID:Distribution of PINK1 and LRRK2 in rat and mouse brain. 1677 36

Alteration G2019S in the leucine-rich repeat kinase 2 gene (LRRK2) has been identified in several populations of patients with parkinsonism, including Ashkenazi Jewish subjects with Parkinson disease. Mutations in glucocerebrosidase (GBA), the enzyme deficient in Gaucher disease, are also identified at an increased frequency among Parkinson probands, including those of Ashkenazi Jewish ancestry. A Taqman Assay-by-Design SNP genotyping strategy was utilized to establish whether G2019S was found in association with GBA mutations. Among 37 subjects with parkinsonism who were heterozygous for a GBA mutation, none carried G2019S. Furthermore, G2019S was not found in 18 patients with Gaucher disease who developed parkinsonian manifestations and 11 other Gaucher probands with parkinsonism in a first degree relative. Among 45 patients with Gaucher disease without a history of parkinsonism, one G2019S carrier was found. These findings suggest that GBA and LRRK2 mutations are discrete risk factors for parkinsonism in both Ashkenazi Jewish and non-Jewish subjects.
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PMID:Glucocerebrosidase mutations are not found in association with LRRK2 G2019S in subjects with parkinsonism. 1678 Oct 64

Since the first description of Parkinson's disease (PD) in 1817 attempts have been made to resolve the etiology of this common neurodegenerative disorder. In the last century the influence of heredity in PD was controversial. The identification of mutations in six genes responsible for Mendelian forms of PD; alpha-synuclein (SNCA), parkin (PRKN), ubiquitin C-terminal hydrolase L1 (UCH-L1), oncogene DJ-1, PTEN-induced putative kinase 1 (PINK1), and most recently leucine-rich repeat kinase 2 (LRRK2), has confirmed the role of genetics in familial forms of the disease. The exact relationship of these familial disorders and related genes to the more common sporadic form is currently uncertain. The identification of LRRK2 mutations and the association of common variants in SNCA and UCH-L1 in apparently sporadic late-onset disease indicate these genes may be of greater importance than previously believed. The protein products of the six genes are involved in different pathways of neurodegeneration and have opened new avenues of research. This focused research will lead to the development of novel targeted therapies, which may revolutionize the treatment of PD for a substantial proportion of patients.
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PMID:Parkinson's disease: the genetics of a heterogeneous disorder. 1679 86

Parkinson's disease (PD) is the most common form of parkinsonism, affecting nearly 2% of people older than 65 years of age. Symptomatic treatment has been available for decades, but to date there is no treatment retarding disease progression. Over the past decade several genes causing parkinsonism have been identified in families with a mendelian pattern of inheritance. The most recent is the leucine-rich repeat kinase 2 (LRRK2) gene. Pathogenic mutations in the LRRK2 gene cause a significant proportion of clinically typical, late-onset PD. This review summarizes the current knowledge on the contribution of LRRK2 mutations in understanding parkinsonism.
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PMID:PARK8 LRRK2 parkinsonism. 1682 48


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