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)

Mutations in GBA gene have been reported to be in patients with Parkinson's disease (PD) from different ethnic populations, including Taiwanese Chinese. To explore whether mutation in GBA is also associated with PD in Mainland China, we have now a case control study. The occurrence of the GBA L444P mutation was analyzed in an independent cohort of PD patients and controls from Mainland China. This mutation was present in 20/616 (3.2%) of PD compared with 1/411 (0.2%) of controls (odds ratio, OR=13.76, 95% Confidence interval, CI: 1.84-102.92, p=0.001). All carriers harbored the heterozygous genotype. In a subset analysis, the frequency of this mutation was higher both in early onset (EOPD) and late onset PD (LOPD) than in controls. However, no difference in clinical characteristics, such as gender, age at onset, onset symptoms, Hoehn-Yahr stage and UPDRS, was found between L444P carriers and non-carriers. In addition, we also explored the potential relationship between GBA L444P mutation and LRRK2 G2385R and R1628P variants in patients with PD. But no association was found, either. In conclusion, our data suggest that the GBA L444P mutation plays an important role in the development of PD also in Han-Chinese patients from Mainland China.
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PMID:Association between GBA L444P mutation and sporadic Parkinson's disease from Mainland China. 2000 3

Parkinson's disease (PD) is the most common neurodegenerative disease after Alzheimer's disease. Although the pathogenetic mechanisms underlying PD is largely unknowm, it is widely believed that multiple genetic as well as environmental factors play critical roles in the development of PD. Alpha synuclein (a-SYN) and the disturbance of a-SYN metabolism seems to play the most important role in PD pathogenesis. a-SYN, the gene causative in PARK1, is the major component of Lewy bodies. Gene duplication or triplication of a-SYN leads to autosomal dominant form of familial PD, suggesting that disturbance of a-SYN may represent the etiology of sporadic PD. GBA and LRRK, the genes responsible for Gaucher disease and PARK8, respetively, are also likely to affect the development of PD. Studies of PD brains suggest that mitochondrial impairment and oxidative stress may contribute to the pathogenesis of sporadic PD. Mitochondrial complex I inhibitors, such as MPTP and rotenone, induce selective dopaminergic neuronal death, suggesting that chemicals may constitute risk factors of sporadic PD. Not only continuous infusion, but oral intake of rotenone is effective to establish animal models of PD. Further studies will reveal genetic or environmental risk factors, that are the good targets for prevention and therapy of PD.
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PMID:[Pathogenesis of sporadic Parkinson's disease: contribution of genetic and environmental risk factors]. 2003 Feb 38

An association between mutations in the glucocerebrosidase (GBA) gene and Parkinson's disease (PD) has been reported in several populations. We searched for four common GBA mutations (L444P, F213I, R353W, and N370S) in 402 Chinese PD patients and 413 age- and sex-matched controls. In the PD cohort, 11 patients were found carrying a heterozygous GBA mutation and all of them had the L444P mutation. Heterozygous GBA mutations were detected none in controls. The GBA gene L444P mutation was detected at a significantly higher frequency among PD patients (11/402 = 2.74%), when compared with the control group (0/413): P = 0.0007. To evaluate the possible role of the GBA gene L444P mutation in PD in Ashkenazi Jewish and non-Jewish populations, we conducted a meta-analysis on the topic. In the Chinese population, the GBA gene L444P mutation was detected at a significantly higher frequency among PD patients, when compared with the control group: Z = 3.83, P = 0.0001, OR = 8.42, confidence interval = 95%, 2.83-25.06. In the non-Jewish populations, the difference was obviously significant: Z = 5.76, P < 0.00001, OR = 8.82, confidence interval = 95%, 4.21-18.48. The results suggest that the GBA gene L444P mutation appears to be a risk factor for PD in Chinese population.
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PMID:Glucocerebrosidase gene L444P mutation is a risk factor for Parkinson's disease in Chinese population. 2013 88

In Gaucher disease, defective lysosomal glucocerebrosidase due to mutations in the GBA1 gene results in lysosomal accumulation of glucocerebroside in mononuclear phagocytes and a multisystemic phenotype. Observations of occurrence of Parkinson's disease in some patients with non-neuronopathic type 1 Gaucher disease (GD1) and their first degree relatives has led to the identification of GBA1 heterozygous mutations as a genetic risk factor for idiopathic Parkinson's disease (PD). However, the magnitude of risk of PD in patients with known GD1 has not been determined, and it is not known whether GD1/PD represents a specific sub-phenotype of GD1 with distinctive genotype/phenotype characteristics. We estimated the risk of PD in a cohort of 444 consecutively evaluated patients with GD1 compared to that in the general population. Eleven patients developed parkinsonian syndrome during a 12-year follow-up period. The adjusted life-time risk ratio of PD in GD1 compared to that in the general population was 21.4 [95% confidence interval (95% CI) 10.7-38.3], with a higher risk in men compared to women. In our cohort, GD1/Parkinson's disease phenotype (GD1/PD) was characterized by higher GD1 severity score, due to higher incidence of avascular osteonecrosis. The clinical spectrum of PD varied from mild to potentially life-threatening disease. All but one patient with GD1/PD phenotype had at least one N370S GBA1 allele. In conclusion, compared to the general population, patients with GD1 have an almost 20-fold increased life-time risk of developing PD.
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PMID:The risk of Parkinson's disease in type 1 Gaucher disease. 2017 87

While little is known about risk factors for cognitive impairment in early onset Parkinson disease (EOPD), postmortem studies have shown an association between dementia with Lewy bodies (DLB) and glucocerebrosidase (GBA) mutation. We compared Mini-Mental State Examination (MMSE) performance and self-reported cognitive impairment in 699 EOPD participants genotyped for mutations in parkin (PRKN), leucine-rich repeat kinase-2 (LRRK2), and GBA. Logistic regression was used to assess the association between reported cognitive impairment and MMSE score, as well as between GBA group membership and self-reported impairment and MMSE. GBA carriers reported more impairment, but MMSE performance did not differ among genetic groups. Detailed neuropsychological testing is required to explore the association between cognitive impairment and GBA mutations.
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PMID:Self-report of cognitive impairment and mini-mental state examination performance in PRKN, LRRK2, and GBA carriers with early onset Parkinson's disease. 2018 43

Mutations in the gene encoding glucocerebrosidase (GBA), the enzyme deficient in the lysosomal storage disorder Gaucher disease, are associated with the development of Parkinson disease and other Lewy body disorders. In fact, GBA variants are currently the most common genetic risk factor associated with parkinsonism, and identified subjects with Parkinson disease are more than five times more likely to carry mutations in GBA. The mechanisms underlying this association are not known, but proposed theories include enhanced protein aggregation, alterations in lipid levels, and autophagy-lysosomal dysfunction promoting the retention of undegraded proteins. We review the genetic studies linking GBA to parkinsonism, as well as several of the mechanisms postulated to explain the association of GBA mutations and the synucleinopathies, which demonstrate how studies of a rare mendelian disease may provide insights into our understanding of a common complex disorder.
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PMID:The role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders. 2042 34

We have recently found that multiple rare variants of the glucocerebrosidase gene (GBA) confer a robust risk for Parkinson disease, supporting the 'common disease-multiple rare variants' hypothesis. To develop an efficient method of identifying rare variants in a large number of samples, we applied multiplexed resequencing using a next-generation sequencer to identification of rare variants of GBA. Sixteen sets of pooled DNAs from six pooled DNA samples were prepared. Each set of pooled DNAs was subjected to polymerase chain reaction to amplify the target gene (GBA) covering 6.5 kb, pooled into one tube with barcode indexing, and then subjected to extensive sequence analysis using the SOLiD System. Individual samples were also subjected to direct nucleotide sequence analysis. With the optimization of data processing, we were able to extract all the variants from 96 samples with acceptable rates of false-positive single-nucleotide variants.
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PMID:Multiplexed resequencing analysis to identify rare variants in pooled DNA with barcode indexing using next-generation sequencer. 2048 46

Among the genes implicated for parkinsonism is glucocerebrosidase (GBA), which causes Gaucher disease (GD). Despite a growing literature that GD may present as parkinsonism, neuroimaging, olfaction, and neuropsychological testing have not been extensively reported. We describe transcranial sonography (TCS), 18F-fluorodopa (F-dopa) and fluorodeoxyglucose (FDG) Positron emission tomography, olfaction testing, neuropsychological testing, and clinical features in homozygous and compound heterozygous GBA mutation carriers identified through screening of 250 Ashkenazi Jewish parkinsonian individuals treated at a tertiary care center. We identified two individuals with N370S/R496H compound heterozygous mutations and two with N370S homozygous mutations; one individual died before completing detailed evaluation. TCS (n = 3) demonstrated nigral hyperechogenicity that was greater than controls [median area maximal substantia nigra echogenicity (aSNmax) = 0.28 cm(2) vs. 0.14 cm(2), P = 0.005], but similar to idiopathic PD (aSNmax = 0.31 cm(2)). FDG PET (n = 2) demonstrated hypermetabolism of the lentiform nuclei, and F-fluorodopa PET (n = 2), bilateral reduction in striatal F-dopa uptake. Olfaction was markedly impaired in the two tested cases, including onset of smell disturbance in adolescence in one. Neuropsychological features (n = 3) were consistent with Parkinson's disease (PD) or diffuse Lewy body disease (DLB). The imaging, neuropsychological and olfactory markers suggest the GD phenotype includes PD with and without features of DLB, marked olfactory loss, nigral hyperechogenicity on TCS, and F-dopa and FDG PET abnormalities.
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PMID:Gaucher disease ascertained through a Parkinson's center: imaging and clinical characterization. 2062 26

Gaucher disease (GD), a sphingolipidosis characterized by impaired activity of the lysosomal enzyme glucocerebrosidase (GCase), results from mutations in the GCase-encoding gene, GBA. We have shown that mutant GCase variants present variable degrees of endoplasmic reticulum (ER) retention and undergo ER-associated degradation (ERAD) in the proteasome. Furthermore, the degree of ERAD of mutant GCase variants correlates with and is one of the factors that determine GD severity. An association between GD and Parkinson disease (PD) has been demonstrated by the concurrence of PD in GD patients and the identification of GCase mutations in probands with sporadic PD. One of the genes involved in PD is PARK2, encoding the E3 ubiquitin ligase parkin. Parkin functions in the ERAD of misfolded ER proteins, and it is upregulated by unfolded protein response. Loss of parkin function leads to the accumulation of its substrates, which is deleterious to dopaminergic neurons in PD. We, therefore, tested the possibility that the association between GD and PD reflects the fact that parkin acts as an E3 ligase of mutant GCase variants. Our results showed that mutant GCase variants associate with parkin. Normal parkin, but not its RING finger mutants, affects the stability of mutant GCase variants. Parkin also promotes the accumulation of mutant GCase in aggresome-like structures and is involved in K48-mediated polyubiquitination of GCase mutants, indicating its function as its E3 ligase. We suggest that involvement of parkin in the degradation of mutant GCase explains the concurrence of GD and PD.
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PMID:Interaction between parkin and mutant glucocerebrosidase variants: a possible link between Parkinson disease and Gaucher disease. 2064 91

Mutations in the glucocerebrosidase gene (GBA) increase the risk for Parkinson's disease and are also associated with an earlier onset of the disease and an akinetic parkinsonian phenotype. To investigate the underlying pathogenesis of this condition, we assessed cerebral metabolism using positron emission tomography (PET) in GBA mutation carriers with and without parkinsonism. [(18)F]-fluorodeoxyglucose (FDG)-PET using a three-dimensional stereotactic surface projection analysis was used to measure the cerebral metabolic rates of glucose (CMRGlc) in a patient with parkinsonism and Gaucher disease (GD) and five subjects with a heterozygous GBA mutation, including three patients with parkinsonism and three asymptomatic carriers in comparison to 10 healthy controls in the same age range. Dopaminergic neuronal activity was investigated using [(11)C] CFT- and [(11)C] raclopride-PET. All GBA mutation carriers displayed a significant CMRGlc decrease in the supplemental motor area (SMA). The carriers with parkinsonism showed additional hypometabolism in the parietooccipital cortices. The CFT and raclopride PET images in the asymptomatic carriers demonstrated the CFT binding to be within normal values in the putamen and a significant increase was observed in the caudate nucleus while raclopride binding in the striatum was in the normal range. An advanced parkinsonian carrier showed decreased CFT binding and increased raclopride binding in the striatum. The decreased CMRGlc in the SMA was characteristic of the GBA mutation carriers. The hypometabolism in the SMA may, therefore, be involved in the clinical characteristics of parkinsonism associated with GBA mutations when the carriers manifest parkinsonism.
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PMID:Functional brain imaging in glucocerebrosidase mutation carriers with and without parkinsonism. 2066 67


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