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)

Parkinson disease (PD) and dystonia are two major part of neurodegenerative disorders. The underlying cause of PD development has been considered to be a combination of genetic factors and environmental substrates. In case of dystonia, which includes primary sporadic dystonia, such as task specific dystonia, cervical dystonia and so on, are also considered to associate with unknown vulnerable genetic factors. In this paper, the clinical features and causative genes for PD and dystonia were described; especially in particular, the description of those genes associated with the PARK and DYT series were provided. Most of the identified causative genes for PD are associated with the protein degradation and cell death process via convergent mechanisms such as ubiquitin-proteasome system, mitochondrial dysfunction, oxidative stress, and lysosomal system (autophagia). On the other hand, the pathogenic mechanism for dystonia is gradually discovered to be divergent suggested by identified genes, such as torsinA, GCH1, etc, which is compatible and well understood with the divergent expression of dystonia phenotype. Another breakthroughs are required to investigate the treatment of both PD and dystonia based on the pathogenic mechanisms.
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PMID:[Causative gene and its associated gene for Parkinson disease and dystonia]. 1937 15

Genetic analysis has identified many loci designated as PARK loci (OMIM #168600). Many of these loci do not refer to idiopathic Parkinson's disease which is characterized by Lewy body pathology, but rather to clinical parkinsonisms. In this review, besides reviewing the genetic of the disorder, we argue that this designation is misleading and that if we seek to understand the pathogenesis, we should study the genetics of Lewy body diseases: these include not only idiopathic Parkinson's disease, but also such disparate syndromes as Hallevorden-Spatz disease and Niemann-Pick Type C.
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PMID:The genetics of Parkinson's syndromes: a critical review. 1941 54

A body of work has emerged over the past decade demonstrating a relationship between mutations in glucocerebrosidase gene (GBA), the gene implicated in Gaucher disease (GD), and the development of parkinsonism. Several different lines of research support this relationship. First, patients with GD who are homozygous for mutations in GBA have a higher than expected propensity to develop Parkinson's disease (PD). Furthermore, carriers of GBA mutations, particularly family members of patients with GD, have displayed an increased rate of parkinsonism. Subsequently, investigators from centers around the world screened cohorts of patients with parkinsonism for GBA mutations and found that overall, subjects with PD, as well as other Lewy body disorders, have at least a fivefold increase in the number of carriers of GBA mutations as compared to age-matched controls. In addition, neuropathologic studies of subjects with parkinsonism carrying GBA mutations demonstrate Lewy bodies, depletion of neurons of the substantia nigra, and involvement of hippocampal layers CA2-4. Although the basis for this association has yet to be elucidated, evidence continues to support the role of GBA as a PD risk factor across different centers, synucleinopathies, and ethnicities. Further studies of the association between GD and parkinsonism will stimulate new insights into the pathophysiology of the two disorders and will prove crucial for both genetic counseling of patients and family members and the design of relevant therapeutic strategies for specific patients with parkinsonism.
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PMID:The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism. 1942 57

GBA and LRRK2 mutations increase susceptibility to Parkinson disease (PD), which is characterized by various disabling symptoms. An extended cohort of 600 Ashkenazi PD patients was screened for the LRRK2 G2019S and for eight GBA mutations. Reported initial symptoms were compared between three genotypic groups of patients: carriers of GBA mutations, carriers of LRRK2 G2019S mutation, and non-carriers. More LRRK2 G2019S carriers reported muscle stiffness (rigidity, p = 0.007) and balance disturbances (p = 0.008), while more GBA mutation carriers reported slowness (bradykinesia, p = 0.021). These results suggest distinct effects of LRRK2 or GBA mutations on the initial symptoms of PD.
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PMID:LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease. 1945 69

Parkinson's disease is a common progressive bradykinetic disorder that can be accurately diagnosed. It is characterised by the presence of severe pars-compacta nigral-cell loss, and accumulation of aggregated alpha-synuclein in specific brain stem, spinal cord, and cortical regions. The main known risk factor is age. Susceptibility genes including alpha-synuclein, leucine rich repeat kinase 2 (LRRK-2), and glucocerebrosidase (GBA) have shown that genetic predisposition is another important causal factor. Dopamine replacement therapy considerably reduces motor handicap, and effective treatment of associated depression, pain, constipation, and nocturnal difficulties can improve quality of life. Embryonic stem cells and gene therapy are promising research therapeutic approaches.
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PMID:Parkinson's disease. 1952 82

The etiology of Parkinson disease (PD) is multifactorial and is likely to involve different causes in different patients. Several different genes have been identified as causes of familial PD, including alpha-synuclein gene mutations and multiplications, and mutations of parkin, PINK1, DJ1, and LRRK2. The biochemical consequences of these mutations have served to reinforce the relevance of the pathways to pathogenesis previously characterized, for example, mitochondrial dysfunction, oxidative stress, and protein misfolding and aggregation. The recognition that glucocerebrosidase mutations represent a significant risk factor for PD has focused attention on lysosomal function and autophagy as relevant to PD. Several environmental factors have also been shown to influence the risk for PD, although odds ratios remain relatively modest. Specific toxins can cause dopaminergic cell death in man and animals, but they probably have limited relevance to the etiology of PD.
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PMID:Etiology and pathogenesis of Parkinson disease. 1955 23

A growing body of experimental and clinical literature indicates an association between Gaucher disease and parkinsonism, raising the possibility that convergent mechanisms may contribute to neurodegeneration in these disorders. The aim of this study was to determine whether there is a relationship between alpha-synuclein (alpha-syn), a key protein in Parkinson's disease pathogenesis, and abnormalities in glucocerebroside (GC) catabolism that lead to the development of Gaucher disease. We inhibited glucocerebrosidase (GCase) with conduritol B epoxide (CBE) in neuroblastoma cells and mice to test whether a biological link exists between GCase activity and alpha-syn. After CBE exposure, enhanced alpha-syn protein was detected in differentiated cells challenged with CBE as compared to vehicle, with no change in alpha-syn mRNA. In the mouse model, after one injection of CBE, elevated nigral alpha-syn levels were also detected. Analyses by Western blot and confocal microscopy revealed that normal alpha-syn distribution was perturbed after CBE exposure with its accumulation apparent within nigral cell bodies as well as astroglia. These findings raise the possibility that alpha-syn may contribute to the cascade of events that promote neuronal dysfunction in Gaucher disease and are the first to implicate this protein as a plausible biological intersection between Gaucher disease and parkinsonism using a pharmacological model.
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PMID:Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: a biological link between Gaucher disease and parkinsonism. 1957 30

In the past decade, a number of genetic causes of parkinsonism have been identified. As a consequence, clinicians have to consider an increasing range of differential diagnoses when confronted with a patient with parkinsonism with a positive family history. While well-established monogenic forms with PARK acronyms have been reviewed extensively, less emphasis has been placed on other inherited conditions that may also present with signs of parkinsonism or even mimic idiopathic Parkinson's disease clinically. In this review, we focus on three different scenarios in patients with an overall early age of onset of parkinsonism: (i) atypical features in patients with mutations in one of the "PARK" genes; (ii) classical parkinsonism due to mutations in "other than-PARK" genes or yet other genes where parkinsonism may be a well-recognized, concomitant, or even an isolated feature; (iii) atypical parkinsonism in other genetic disorders which are, however, typically characterized by features other than parkinsonism. Atypical features in patients from Group I include, for example, a slower disease course (PARK2, PARK6, PARK7) or dementia (PARK1/4, PARK14). Conditions in Group II have been designated by a DYT or SCA acronym (for example, DYT5 or SCA3) and also include patients with heterozygous GBA mutations, mitochondrial gene mutations. Group III comprises mutations in the FMR1, MAPT, GRN, ATP7B, PANK2, FBXO7, CHAC, FTL1, Huntingtin, JPH3 genes, and a number of even rarer, miscellaneous conditions.
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PMID:Hereditary parkinsonism: Parkinson disease look-alikes--an algorithm for clinicians to "PARK" genes and beyond. 1973 92

Mutations in the Parkin (PARK2) and PINK1 gene (PARK 6) can cause recessively inherited Parkinson's disease (PD). The presence of a single Parkin or PINK1 mutation is associated with a dopaminergic nigrostriatal dysfunction and conveys an increased risk to develop PD throughout lifetime. Therefore neuroimaging of non-manifesting individuals with a mutant Parkin or PINK1 allele opens up a window for the investigation of preclinical and very early phases of PD in vivo. Here we review how functional magnetic resonance imaging (fMRI) can be used to identify compensatory mechanisms that help to prevent development of overt disease. In two separate experiments, Parkin mutation carriers displayed stronger activation of rostral supplementary motor area (SMA) and right dorsal premotor cortex (PMd) during a simple motor sequence task and anterior cingulate motor area and left rostral PMd during internal movement selection as opposed to externally cued movements. The additional recruitment of the rostral SMA and right rostral PMd during the finger sequence task was also observed in a separate group of nonmanifesting mutation carriers with a single heterozygous PINK1 mutation. Because mutation carriers were not impaired at performing the task, the additional recruitment of motor cortical areas indicates a compensatory mechanism that effectively counteracts the nigrostriatal dysfunction. These first results warrant further studies that use these imaging genomics approach to tap into preclinical compensation of PD. Extensions of this line of research involve fMRI paradigms probing nonmotor brain functions. Additionally, the same fMRI paradigms should be applied to nonmanifesting mutation carriers in genes linked to autosomal dominant PD. This will help to determine how "generically" the human brain compensates for a preclinical dopaminergic dysfunction.
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PMID:Mapping preclinical compensation in Parkinson's disease: an imaging genomics approach. 1987 38

Mutations in the glucocerebrosidase gene (GBA) have recently been associated with an increased risk of Parkinson disease (PD). GBA mutations have been observed to be particularly prevalent in the Ashkenazi Jewish population. Interestingly, this population also has a high incidence of the Lrrk2 p.G2019S mutation which is similar in North African Arab-Berber populations. Herein, our sequencing of the GBA gene, in 33 North African Arab-Berber familial parkinsonism probands, identified two novel mutations in three individuals (p.K-26R and p.K186R). Segregation analysis of these two variants did not support a pathogenic role. Genotyping of p.K-26R, p.K186R and the common p.N370S in an ethnically matched series consisting of 395 patients with PD and 372 control subjects did not show a statistically significant association (P>0.05). The p.N370S mutation was only identified in 1 sporadic patient with PD and 3 control subjects indicating that the frequency of this mutation in the North African Arab-Berber population is much lower than that observed in Ashkenazi Jews, and therefore arose in the latter after expansion of the Lrrk2 p.G2019S variant in North Africa.
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PMID:Glucocerebrosidase mutations are not a common risk factor for Parkinson disease in North Africa. 1994 10


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