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)

Lewy body has been linked to Parkinson's disease for almost a century, but its significance in neurodegenerative diseases is not known. Whether it is toxic, protective, or just a bystander has been a subject of debate. Recent advances in molecular and genetic works suggest Lewy bodies are not essential for the diagnosis and pathogenesis of Parkinson's disease. Furthermore, the discovery of gene mutations in PARK8, an autosomal-dominant late-onset parkinsonism with pleomorphic pathology, suggests the clinical expression of neurodegenerative diseases depends more on the anatomical pathways affected rather than any particular "pathological marker".
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PMID:A reassessment of the Lewy body. 1600 61

Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa (18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(+/-)-dihydrotetrabenazine (11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate (11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.
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PMID:PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation. 1631 Dec 69

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Some debate still exists as to whether PD is predominantly environmental or genetic in etiology. The genetic hypothesis of PD etiology has been driven recently by the identification of a number of PD loci. This review deals with each of these loci, discussing the latest data and evidence available. Of particular interest are the recently described mutations in the PINK1 (PARK6) and LRRK2 (PARK8) genes. We also consider the impact of these latest developments on our understanding of sporadic PD and on our everyday practice with PD patients.
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PMID:Genetics of parkinsonism. 1613 23

Multiple mutations in the gene for the leucine-rich repeat kinase (LRRK2) cause autosomal dominant late-onset parkinsonism (PARK8). The Gly2019Ser mutation appears to be common in different populations. To investigate whether this novel gene influences the non-Mendelian sporadic form of Parkinson's disease, we genotyped 121 single nucleotide polymorphisms comprehensively covering the entire LRRK2 gene region in a set of 340 Parkinson's disease patients and 680 matched control subjects from Germany. No association could be demonstrated. We have therefore no evidence for the existence of a common variant in LRRK2 that has a strong influence on Parkinson's disease risk.
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PMID:Common variants of LRRK2 are not associated with sporadic Parkinson's disease. 1625 73

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

We measured striatal dopamine transporter binding using [(123)I]ioflupane and SPECT in patients with Parkinson's disease associated with the LRRK2 (PARK8) Gly2019Ser gene mutation (LRRK2-PD) and in gene-negative patients with idiopathic Parkinson's disease (IPD) of comparable disease duration and severity. The LRRK2-PD group consisted of a total of 10 patients (3 sporadic) with mean age 62 +/- 14 years, disease duration 9 +/- 3 years, and UPDRS III motor score 21.60 +/- 6.65. The control IPD group consisted of 15 patients with mean age 59 +/- 9 years, disease duration 9 +/- 5 years, and UPDRS III motor score 23.80 +/- 8.69. [(123)I]ioflupane-specific uptake ratios were calculated for caudate nucleus and putamen using the occipital cortex as reference region. We found no differences between the LRRK2-PD group and IPD in all items studied. In particular, putamen and caudate uptake values as well as side asymmetry indexes and putamen/caudate ratios all revealed comparable between-group values. We conclude that in these patients carrying the LRRK2 Gly2019Ser mutation, the neurodegenerative process results in a pattern of nigrostriatal dopaminergic dysfunction similar to that observed in IPD.
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PMID:Striatal dopamine transporter binding in Parkinson's disease associated with the LRRK2 Gly2019Ser mutation. 1667 Oct 78

The etiology for Parkinson's disease (PD) remains unknown. Genetic causes have been identified with several distinct mutations. Recently, 9 mutations involving a novel gene, leucine-rich repeat kinase 2 (LRRK2), have been identified as the cause of autosomal dominant PD in kindreds, with some of them previously linked to the PARK8 locus on chromosome 12. LRRK2 mutations are relatively common genetic causes of familial and sporadic PD. In addition, these mutations have been identified in diverse populations. The clinical and pathologic features of LRRK2-associated PD are indistinguishable from idiopathic PD; however, considerable clinical and pathologic variability exists even among kindreds. This short review highlights the clinical and pathologic features in LRRK2-associated parkinsonism.
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PMID:Clinical and pathologic features of families with LRRK2-associated Parkinson's disease. 1701 33

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) have been identified as the cause of familial Parkinson's disease (PD) at the PARK8 locus. To begin to understand the physiological role of LRRK2 and its involvement in PD, we have investigated the distribution of LRRK2 mRNA and protein in the adult mouse brain. In situ hybridization studies indicate sites of mRNA expression throughout the mouse brain, with highest levels of expression detected in forebrain regions, including the cerebral cortex and striatum, intermediate levels observed in the hippocampus and cerebellum, and low levels in the thalamus, hypothalamus and substantia nigra. Immunohistochemical studies demonstrate localization of LRRK2 protein to neurones in the cerebral cortex and striatum, and to a variety of interneuronal subtypes in these regions. Furthermore, expression of LRRK2 mRNA in the striatum of VMAT2-deficient mice is unaltered relative to wild-type littermate controls despite extensive dopamine depletion in this mouse model of parkinsonism. Collectively, our results demonstrate that LRRK2 is present in anatomical brain regions of direct relevance to the pathogenesis of PD, including the nigrostriatal dopaminergic pathway, in addition to other regions unrelated to PD pathology, and is likely to play an important role in the normal function of telencephalic forebrain neurones and other neuronal populations.
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PMID:Expression and localization of Parkinson's disease-associated leucine-rich repeat kinase 2 in the mouse brain. 1710 Oct 29

Leucine-rich repeat kinase 2 (LRRK2), a product of a causative gene for the autosomal-dominant form of familial Parkinson's disease (PARK8), harbors a Ras-like small GTP binding protein-like (ROC) domain besides the kinase domain, although the relationship between these two functional domains remains elusive. Here we show by thin-layer chromatographic analysis that LRRK2 stably binds GTP but lacks a GTPase activity in HEK293 and Neuro-2a cells. A ROC domain mutation that converts LRRK2 to a guanine nucleotide-free form (T1348N) abolishes the kinase activity of LRRK2 as well as its phosphate incorporation upon metabolic labeling. The phosphorylation of LRRK2 was inhibited by potential inhibitors for cyclic AMP-dependent protein kinase. These data suggest that binding of GTP to the ROC domain regulates the kinase activity of LRRK2 as well as its phosphorylation by other kinase(s).
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PMID:GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. 1726 Sep 67

We tested the hypothesis that parkin polymorphisms (SNPs) and environmental exposure (EE) interact to reduce the age of onset of idiopathic Parkinson disease (PD). We prospectively and consecutively enrolled a total of 81 Italian PD patients. The diagnosis of PD was based on the UK Parkinson's Disease Society's brain bank criteria. Twenty-one patients with a positive family history for PD or tremor were excluded from the study. We collected information about medical history and EE. PARK1, PARK2 genes and PARK8 (exon 41) were screened. We detected one parkin mutation in a single patient and three parkin polymorphisms in a total of 25 patients; no alpha synuclein mutations, no common mutations of LRKK2 gene were found. The mutation-positive patient has been excluded from the study. The cohort of the remaining 59 patients has been divided into four subgroups, according to the presence/absence of parkin polymorphisms and the presence/absence of environmental factors-exposure. The age of onset of PD was significantly lower in patients with both SNPs and EE as compared to patients without (62.18+/-9.5 years versus 71.62+/-8 years, p=0.024; -13%). Patients with either SNPs or EE had an intermediate age of onset. The association of parkin polymorphisms and environmental exposure has a strong effect in lowering the age of onset of PD; the effect of environmental exposure or parkin polymorphisms alone seems to influence modestly the age of onset of PD. Individuals with environmental/occupational exposure should be screened for the presence of parkin SNPs.
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PMID:Parkin polymorphisms and environmental exposure: decrease in age at onset of Parkinson's disease. 1733 4


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