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)

Proteolytic degradation of unwanted proteins by the ubiquitin-proteasome system (UPS) is critical for normal maintenance of various cellular functions. Parkinson's disease (PD), one of the most prevalent neurodegenerative disorders, is characterized by prominent and irreversible nigral dopaminergic neuronal loss and intracellular protein aggregations. Epidemiological studies imply both environmental neurotoxins and genetic predisposition as potential risk factors for PD, though mechanisms underlying selective dopaminergic degeneration remain unclear. Studies with experimental PD models and postmortem PD brains have provided explicit evidence for mitochondria dysfunction and oxidative stress in PD pathogenesis. Recent identification of mutants in PINK1, DJ-1, Parkin, and LRRK-2 genes compliments the oxidative stress and mitochondrial dysfunction hypotheses in dopaminergic neuronal degeneration in PD. Mutants of alpha-synuclein, Uch-L1 and Parkin support the involvement of UPS dysfunction in PD. Furthermore, various Parkinsonian toxicants have been shown to impair mitochondrial function, redox balances, and to some extent protein degradation machinery. Because environmental exposure to various neurotoxic agents is considered a dominant risk for development of PD, the interrelationship between neurotoxicant exposures and UPS dysfunction must be clearly understood. Elucidation of this interrelationship will help clarify 2 areas: (i) whether UPS dysfunction in PD is a primary pathogenic factor leading to nigral neuronal death or if it simply occurs as a consequence of oxidative stress and mitochondrial dysfunction and (ii) the interaction of genes and environment in the acceleration of nigral dopaminergic degeneration by targeting UPS. We review the recent evidence for UPS deficits in dopaminergic degeneration triggered by neurotoxins.
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PMID:Environmental neurotoxic chemicals-induced ubiquitin proteasome system dysfunction in the pathogenesis and progression of Parkinson's disease. 1752 40

The past 10 years has seen a shift in our etiological concepts of Parkinson's disease, moving from a nearly exclusively environmentally mediated disease towards a complex disorder with important genetic contributors. The identification of responsible mutations in certain genes, particularly alpha-synuclein, Parkin, PINK1, DJ-1 and LRRK2, has increased our understanding of the clinical and pathological changes underlying Parkinson's disease, with implications for patient diagnosis, management and future research. This review will outline the specific genetic advances, discuss their implications for clinical practice and hint at future directions for research into this common and disabling disease.
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PMID:Genetics of Parkinson's disease and parkinsonism. 1756 49

The association of six genes with monogenic forms of parkinsonism has unambiguously established that the disease has a genetic component. Of these six genes, LRRK2 (leucine-rich repeat kinase 2, or PARK8), parkin (PARK2), and PINK1 (PTEN-induced putative kinase 1, or PARK6) are the most clinically relevant because of their mutation frequency. Insights from initial familial studies suggest that LRRK2-associated parkinsonism is dominantly inherited, whereas parkinsonism linked to parkin or PINK1 is recessive. However, screening of patient cohorts has revealed that up to 70% of people heterozygous for LRRK2 mutations are unaffected, and that more than 50% of patients with mutations in parkin or PINK1 have only a single heterozygous mutation. Deciphering the role of heterozygosity in parkinsonism is important for the development of guidelines for genetic testing, for the counselling of mutation carriers, and for the understanding of late-onset Parkinson's disease. We discuss the roles of heterozygous LRRK2 mutations and heterozygous parkin and PINK1 mutations in the development of parkinsonism, and propose an integrated aetiological model for this complex disease.
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PMID:Deciphering the role of heterozygous mutations in genes associated with parkinsonism. 1758 54

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder and in most patients its aetiology remains unknown. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, and support a major role for mitochondrial dysfunction, which is also of significant importance to the common sporadic forms of PD. While current treatments temporarily alleviate symptoms, they do not halt disease progression. Drugs that target the underlying pathways to PD pathogenesis, including mitochondrial dysfunction, therefore hold great promise for neuroprotection in PD. Here we summarize how the proteins identified through genetic research (alpha-synuclein, parkin, PINK1, DJ-1, LRRK2 and HTRA2) fit into and add to our current understanding of the role of mitochondrial dysfunction in PD. We highlight how these genetic findings provided us with suitable animal models and critically review how the gained insights will contribute to better therapies for PD.
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PMID:Genetic findings in Parkinson's disease and translation into treatment: a leading role for mitochondria? 1768 Aug 6

There is substantial evidence based on well designed epidemiologic studies for low cancer rates in patients with Parkinson disease (PD). This risk reduction cannot be attributed to the recognized low life-long incidence of smoking in patients with PD, as not only smoking-related cancers but also non-smoking-related ones are less common in PD. Whereas the risk for most cancers appears to be relatively low in patients with PD, breast cancer and melanomas occur more frequently in the PD population as compared with controls. The relationship between this peculiar pattern of cancer rates and PD might be related to the involvement of common genes in both diseases. Mutations in parkin gene, for example, have been reported in several types of cancer. Furthermore, genes involved in familial forms of PD appear to be abnormally expressed in cancers. Thus, parkin and PINK1 might be tumor suppressor genes, whereas DJ-1 is an oncogene. Cell survival signals may differ owing to mutated genes and represent two opposite extremes such as cell proliferation in cancer and cell death due to apoptosis in PD. Unraveling the link between PD and cancer may open a therapeutic window for both diseases.
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PMID:Are Parkinson disease patients protected from some but not all cancers? 1900 Dec 59

Studies of familial forms of Parkinson's disease (PD) have identified a growing number of genes that derive from the loci given the nomenclature PARK1-PARK13 (OMIM 168600). The alpha-synuclein gene has been implicated in rare autosomal dominant PD because of either mis-sense mutations (PARK1) or gene multiplications (PARK4). Moreover, UCHL1 (PARK5), LRRK2 (PARK8) and HTRA2 (PARK13) have been identified as causative genes for autosomal dominant PD, whereas parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7) and ATP13A2 (PARK9) have been identified as causative genes for autosomal recessive PD. Neuropathological examination of the kindreds of PARK1/4 showed Lewy body pathology ranging from classic PD to diffuse Lewy body disease. The pathological findings of PARK3 are similar to those of classic PD. In contrast, autopsies of patients with PARK2 showed nigral cell loss without Lewy bodies, although exceptions have been reported. Several kindreds of PARK8 included cases with Lewy body pathology, tau pathology, or with nigral cell loss in the absence of obvious protein deposition. Ubiquitin-positive inclusions that are negative for alpha-synuclein and tau are also seen in some cases. Moreover, widespread Lewy body pathology was also reported in several cases of familial Alzheimer's disease with presenilin-1 mutations.
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PMID:[Pathology of familial Parkinson's disease]. 1771 21

Over the last 10 years, an unprecedented number of scientific reports have been published that relate to the pathogenesis of parkinsonism. Since the discovery in 1997 of the first heritable form of parkinsonism that could be linked to a mutation in a single gene, SNCA, many more genetic leads have followed (Parkin, DJ-1, PINK1, LRRK2, to name a few); these have provided us with many molecular clues to better explore the etiology of parkinsonism and have led to the dismantling of many previously held dogmas about Parkinson disease (PD). Epidemiologic studies have delineated an array of environmental modulators of susceptibility to parkinsonism, which can now be examined in the context of gene expression. Furthermore, in vivo imaging data and postmortem results have generated concepts that greatly expanded our appreciation for the phenotypic spectrum of parkinsonism from its presymptomatic to advanced stages. With this plethora of new information emerged the picture of a complex syndrome that raises many questions: How many forms of classic parkinsonism/Parkinson disease(s) are there? Where does the disease begin? What causes late-onset, "idiopathic" PD? What are the caveats related to genetic testing? What is the role of Lewy bodies? What will be the best disease model to accommodate the now known genetic and environmental contributors to parkinsonism? What will be the ideal markers and targets for earlier diagnosis and cause-directed therapy? In the following article we highlight some of the burning issues surrounding the understanding of classic parkinsonism, a complex puzzle of genes, environment, and an aging host.
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PMID:Parkinson disease, 10 years after its genetic revolution: multiple clues to a complex disorder. 1864 74

In mice, targeted deletion of the serine protease HtrA2 (also known as Omi) causes mitochondrial dysfunction leading to a neurodegenerative disorder with parkinsonian features. In humans, point mutations in HtrA2 are a susceptibility factor for Parkinson's disease (PARK13 locus). Mutations in PINK1, a putative mitochondrial protein kinase, are associated with the PARK6 autosomal recessive locus for susceptibility to early-onset Parkinson's disease. Here we determine that HtrA2 interacts with PINK1 and that both are components of the same stress-sensing pathway. HtrA2 is phosphorylated on activation of the p38 pathway, occurring in a PINK1-dependent manner at a residue adjacent to a position found mutated in patients with Parkinson's disease. HtrA2 phosphorylation is decreased in brains of patients with Parkinson's disease carrying mutations in PINK1. We suggest that PINK1-dependent phosphorylation of HtrA2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress.
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PMID:The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. 1797 47

We report on a patient who developed left arm rest/postural tremor at age 24 and responded well to trihexyphenidyl. One year later spastic paraparesis appeared, and multiple sclerosis was diagnosed on the basis of clinical, radiological, and laboratory evidence. Although paraparesis improved after immunosuppressant therapy, a complete picture of an asymmetric parkinsonian syndrome gradually developed. Excellent response to levodopa, drug-induced dyskinesias, and DaTSCAN revealing pathology congruent with Parkinson's disease (PD) indicate a coincidental etiopathogenetic relationship of both clinical entities: multiple sclerosis and PD. Genetic analyses focusing on autosomal recessive parkinsonism (parkin, DJ1, and PINK1) were negative. To the best of our knowledge, only 15 cases of parkinsonism in association with multiple sclerosis have been reported, and their relationship has been interpreted to be either causal or coincidental. This is the first report of a coincidence of both entities, in which the parkinsonian syndrome developed first and before age 30.
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PMID:A unique case of coincidence of early onset Parkinson's disease and multiple sclerosis. 1791 25

Parkinson's disease (PD) is a common disorder caused by degeneration of dopaminergic neurons in the substantia nigra and other brain areas. Mutations in several genes have been associated with both autosomal dominant PD and recessive early onset Parkinsonism (EOP). Genomic rearrangements such as deletions or multiplications of one or more exons represent a common mutational mechanism for most of these genes and are not detectable with routine mutation screening techniques. MLPA (Multiplex Ligation-dependent Probe Amplification), is a cheap, simple, rapid, and sensitive tool to detect exon dosage alterations and specific point mutations in selected genes. We tested the recently developed PD-MLPA assay by using 13 positive control samples carrying known mutations in SNCA, LRRK2, Parkin, PINK1, and DJ-1 genes. We then applied this technique to screen 16 EOP patients who were then cross-tested by quantitative PCR (qPCR). All the mutations present in the positive control samples were clearly detected by MLPA. Moreover, three novel Parkin rearrangements were identified among EOP patients and confirmed by qPCR. Only two samples generated false positive duplications of LRRK2 exon 1 and UCH-L1 exon 9, respectively. These results show that PD-MLPA assay can simultaneously and effectively detect rearrangements in most PD genes (SNCA, Parkin, PINK1, and DJ-1) as well as the LRRK2 G2019S common mutation. Thus, the use of this novel platform can improve the analysis of such mutations, facilitating comprehensive genetic testing in PD and EOP.
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PMID:Multiplex ligation-dependent probe amplification assay for simultaneous detection of Parkinson's disease gene rearrangements. 1791 26


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