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)

Mutations in PINK1 (PTEN-induced putative kinase 1) are causal for early onset recessive parkinsonism in humans, characterized by damage to the nigrostriatal system. In situ hybridization studies in rodent brains have suggested a predominantly neuronal expression of PINK1 mRNA but immunocytochemistry of human brain tissue has shown PINK1-like immunoreactivity in both neurons and glia. In this study, we assessed the comparative distribution of PINK1 mRNA in human, rat and mouse brain. We observe that in humans PINK1 message is expressed in neurons with very little to no signal in glia and confirms similar findings in rodent tissue. Highest levels of expression were observed in hippocampus, substantia nigra and cerebellar Purkinje cells. We also show that PINK1 mRNA expression is similar in nigral neurons from neurologically normal controls and sporadic Parkinson's disease cases.
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PMID:Expression of PINK1 mRNA in human and rodent brain and in Parkinson's disease. 1795 Feb 57

The PINK1 gene mutation is probably the second most common genetic cause of early-onset Parkinson's disease (EOPD). The frequency and the characteristics of the PINK1 mutation in the Taiwanese population are unknown. This study was designed to investigate the genotype, phenotype and dopaminergic function of PINK1 in a cohort of EOPD patients. The genetic settings were to detect the PINK1 gene mutations in 138 EOPD patients and in 191 controls. Using the (99m)Tc-TRODAT-1 (TRODAT) scan, we investigated the differences in the dopamine transporter (DAT) activities between the PINK1 patients, late-onset Parkinson's disease (LOPD) patients and healthy controls. Four EOPD patients with 3 genotypic mutations in the PINK1 gene were found: a compound heterozygous mutation (Q239X/R492X) in 2 sisters, a novel homozygous mutation (R492X) in a woman, and a novel heterozygous mutation (G193R) in a man. The three PINK1 patients had typical phenotype with juvenile onset, benign course, and frequently with dyskinesias. The TRODAT scan showed a rather even and symmetrical reduction of uptake in PINK1 patients, unlike the dominant decline in the putamen in the LOPD patients. The annual reduction rate of uptake in the striatum was much slower in PINK1 patients than that in the LOPD patients (1.7 % vs. 4.1%; p<0.005). In the patient with a heterozygous mutation in the PINK1 gene, the reduction ratio in the striatum, as well as the annual reduction rate, were closer to those in the LOPD group. We conclude that the incidence of carrying PINK1 mutations in the present cohort of Taiwanese EOPD patients was low, accounting for 2/39 (5.1 %) in familial cases, and 2/99 (2 %) in sporadic cases. The slower annual reduction of DAT activity might indicate the insidious degeneration of dopamine neurons and a benign prognosis.
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PMID:PINK1 mutation in Taiwanese early-onset parkinsonism : clinical, genetic, and dopamine transporter studies. 1796 Mar 43

Myocardial (123)Metaiodobenzylguanidine (MIBG) enables the assessment of postganglionic sympathetic cardiac innervation. MIBG uptake is decreased in nearly all patients with Parkinson's disease (PD). Our objective was to evaluate MIBG uptake in patients with genetic PD. We investigated MIBG uptake in 14 patients with PD associated with mutations in different genes (Parkin, DJ-1, PINK1, and leucine-rich repeat kinase 2 -LRRK2), in 15 patients with idiopathic PD, and 10 control subjects. The myocardial MIGB uptake was preserved in 3 of the 4 Parkin-associated Parkinsonisms, in 1 of the 2 patients with DJ-1 mutations, in 1 of the 2 brothers with PINK1 mutations, in 3 of the 6 unrelated patients with Gly2019Ser mutation in the LRRK2 gene, whereas it was impaired in all patients with idiopathic PD. MIBG was preserved in all control subjects. Our study shows that myocardial MIGB uptake was normal in 8 of 14 patients with genetic PD, suggesting that cardiac sympathetic denervation occurs less frequently in genetic PD than in idiopathic PD. Our findings also demonstrate that MIGB uptake has a heterogeneous pattern in genetic PD, because it was differently impaired in patients with different mutations in the same gene or with the same gene mutation.
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PMID:Myocardial 123metaiodobenzylguanidine uptake in genetic Parkinson's disease. 1797 12

The purpose of this mini-symposium is to discuss some of the inherited forms of Parkinson's disease (PD) in view of recent data suggesting that some of the proteins affect cellular signaling pathways. As an illustration, we shall focus on two different kinases associated with recessive and dominant forms of PD. Mutations in the mitochondrial kinase PTEN (phosphatase and tensin homolog)-induced kinase 1 (PINK1) are loss-of-function mutations in a normally neuroprotective protein. Loss-of-function mutations in model organisms have variable effects, from dramatic muscle and spermatid defects in Drosophila to more subtle neurophysiological abnormalities in mice. Several lines of evidence relate these to the action of a second gene for familial PD, parkin, an E3 ubiquitin ligase shown recently to have effects on Akt signaling. Mutations in leucine-rich repeat kinase 2 (LRRK2), a cytosolic kinase, are dominant and have the opposite effect of causing neuronal damage. The mechanism(s) involved are uncertain at this time because LRRK2 is a large and complex molecule with several domains. Increased kinase activity accounts for the action of at least some of the mutations, suggesting that hyperactive or misregulated kinase activity may lead to the damaging effects of LRRK2 in neurons. For both PINK1 and LRRK2, the following key question that needs to be answered: what are the physiological substrates that mediate effects in cells? Here, we will discuss some of the recent thinking about physiological and pathological roles for signaling in PD and how these may have therapeutic implications for the future.
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PMID:The roles of kinases in familial Parkinson's disease. 1797 26

Degeneration of dopaminergic neurons in the substantia nigra is characteristic for Parkinson's disease (PD), the second most common neurodegenerative disorder. Mitochondrial dysfunction is believed to contribute to the etiology of PD. Although most cases are sporadic, recent evidence points to a number of genes involved in familial variants of PD. Among them, a loss-of-function of phosphatase and tensin homolog-induced kinase 1 (PINK1; PARK6) is associated with rare cases of autosomal recessive parkinsonism. In HeLa cells, RNA interference-mediated downregulation of PINK1 results in abnormal mitochondrial morphology and altered membrane potential. Morphological changes of mitochondria can be rescued by expression of wild-type PINK1 but not by PD-associated PINK1 mutants. Moreover, primary cells derived from patients with two different PINK1 mutants showed a similar defect in mitochondrial morphology. Human parkin but not PD-associated mutants could rescue mitochondrial pathology in human cells like wild-type PINK1. Our results may therefore suggest that PINK1 deficiency in humans results in mitochondrial abnormalities associated with cellular stress, a pathological phenotype, which can be ameliorated by enhanced expression of parkin.
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PMID:Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. 1798 6

Parkinson's disease (PD) is a movement disorder of high prevalence in the elderly. It is characterized by a loss of dopaminergic neurons and the presence of intracytoplasmic inclusions named Lewy bodies. To date six familial PD-associated proteins have been identified so far. Some of them are implicated in the development of either autosomal dominant (alpha-synuclein and LRRK2 (leucine-rich repeat kinase 2/dardarin) or early-onset recessive (parkin, DJ-1, PINK1 (PTEN-induced kinase-1) and ATP13A2) PD forms. A number of genetic studies have shown that 50% of the recessive forms are linked to mutations on parkin gene, followed by PINK1 (8-15%) and DJ-1 (1%). The purpose of this review is to provide an overview of the emerging data on the cellular and molecular biology of DJ-1. DJ-1 is a ubiquitous protein that was first described as an oncogene. Nevertheless, after its association to monogenic PD a number considerable data aiming at understanding its implication in the physiopathology of PD was produced. This review will describe the main advances concerning the function of DJ-1. A considerable progress that was only possible due to a better understanding of DJ-1 structure, genetics, distribution and development of in vivo models. All these points along with the description of recent data showing the interaction of DJ-1 with other PD-associated proteins will be given.
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PMID:DJ-1: a newcomer in Parkinson's disease pathology. 1804 43

Parkinson's disease (PD) is a severe, progressive, age-associated, neurodegenerative disorder. Current therapies are symptomatic and not effective at halting or significantly slowing the disease progress. The search for etiologic-based therapies has focused largely on genetic findings made in familial forms of this disease. Mutations of five genes have been unequivocally linked to PD; two of these, LRRK2 and PINK1, encode kinases and as such are attractive tools with which to understand the disease process; furthermore, preliminary functional data suggests that these proteins, or the pathways in which they are involved, are viable therapeutic targets. Here we explore the current data and thoughts regarding LRRK2 and PINK1 and discuss further avenues of research to understand the pathologic effects of mutations at these loci and potential points of therapeutic intervention, such as within these kinases or in associated pathways such as Jun N-terminal kinase and Akt pathways.
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PMID:Kinase signaling pathways as potential targets in the treatment of Parkinson's disease. 1806 16

There is increasing evidence linking mitochondrial dysfunction to neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. This is the case in Alzheimer's disease, in which there is evidence that both beta-amyloid and the amyloid precursor protein may directly interact with mitochondria, leading to increased free radical production. In the case of Huntington's disease (HD), recent evidence suggests that the coactivator PGC1alpha, a key regulator of mitochondrial biogenesis in respiration, is down-regulated in patients with HD and in several animal models of this neurodegenerative disorder. In Parkinson's disease, the autosomal recessive genes parkin, DJ1 and PINK1 are all linked to either oxidative stress or mitochondrial dysfunction. In amyotrophic lateral sclerosis, there is strong evidence that mutant superoxide dismutase directly interacts with the outer mitochondrial membrane as well as the intermembrane space and matrix. Therefore, an impressive number of disease specific proteins interact with mitochondria. Therapies that target basic mitochondrial processes such as energy metabolism in free radical generation, or specific interactions of disease-related protein with mitochondria, hold great promise.
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PMID:Mitochondria and neurodegeneration. 1807 39

Over the last few years, several genes for monogenic forms of Parkinson's disease (PD) have been mapped and/or cloned. Mutations have been identified in the gene for alpha-synuclein in rare families with dominant PD, indicating that aggregation of this protein in Lewy bodies is probably a crucial step in the molecular pathogenesis of the disorder. A much more common cause for dominant PD, mutations in the gene for leucine-rich repeat kinase 2 (LRRK2), has recently been identified. Mutations in the parkin gene, in DJ-1 and PINK1 all cause autosomal recessive parkinsonism of early onset. These genes have been implicated in the proteasomal protein degradation pathway, in the oxidative stress response and mitochondrial function. Mutations in recessive genes probably are pathogenic through loss-of-function mechanisms, suggesting that their wildtype products protect dopaminergic cells against a variety of insults. Evidence is emerging that at least some of these genes may play a direct role in the etiology of the common sporadic form of PD. Further, it is likely that the cellular pathways identified in rare monogenic variants of the disease also shed light on the molecular pathogenesis in typical sporadic PD.
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PMID:Update on the genetics of Parkinson's disease. 1817 95

Our knowledge regarding the genetics of Parkinson's disease (PD) and parkinsonism has evolved dramatically during the past decade, with the discovery of numerous loci and genes. The LRRK2 gene has emerged as the most commonly involved in both familial and sporadic PD. Several variants in LRRK2 and SNCA have been associated with an increased risk of sporadic PD. PRKN, PINK1 and DJ1 mutations cause early-onset recessively inherited PD. Autosomal dominant dementia and parkinsonism is caused by mutations in the MAPT gene, and in the most recently discovered PGRN gene.
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PMID:Clinical genetics of Parkinson's disease and related disorders. 1826 41


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