Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recessively inherited early-onset parkinsonism (EOP) has been associated with mutations in the Parkin, DJ-1, and PINK1 genes. We studied the prevalence of mutations in all three genes in 65 Italian patients (mean age of onset: 43.2+/-5.4 years, 62 sporadic, three familial), selected by age at onset equal or younger than 51 years. Clinical features were compatible with idiopathic Parkinson's disease in all cases. To detect small sequence alterations in Parkin, DJ-1, and PINK1, we performed a conventional mutational analysis (SSCP/dHPLC/sequencing) of all coding exons of these genes. To test for the presence of exon rearrangements in PINK1, we established a new quantitative duplex PCR assay. Gene dosage alterations in Parkin and DJ-1 were excluded using previously reported protocols. Five patients (8%; one woman/four men; mean age at onset: 38.2+/-9.7 (range 25-49) years) carried mutations in one of the genes studied: three cases had novel PINK1 mutations, one of which occurred twice (homozygous c.1602_1603insCAA; heterozygous c.1602_1603insCAA; heterozygous c.836G>A), and two patients had known Parkin mutations (heterozygous c.734A>T and c.924C>T; heterozygous c.924C>T). Family history was negative for all mutation carriers, but one with a history of tremor. Additionally, we detected one novel polymorphism (c.344A>T) and four novel PINK1 changes of unknown pathogenic significance (-21G/A; IVS1+97A/G; IVS3+38_40delTTT; c.852C>T), but no exon rearrangements. No mutations were found in the DJ-1 gene. The number of mutation carriers in both the Parkin and the PINK1 gene in our cohort is low but comparable, suggesting that PINK1 has to be considered in EOP.
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PMID:PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism. 1597 Sep 50

PD (Parkinson's disease) is an aetiologically heterogeneous disorder characterized by a clinical phenotype consisting of resting tremor, rigidity and bradykinesia. Motor symptoms are associated with a progressive loss of dopaminergic neurons, with Lewy body inclusions within surviving neurons. Although heritability studies have shown evidence of familial aggregation, twin studies have provided limited support for a genetic aetiology. Nevertheless, classical linkage methods have nominated 11 regions of the genome and pathogenic mutations have been identified in several genes, including alpha-synuclein, parkin, ubiquitin C-terminal hydrolase L1, oncogene DJ-1, PTEN-induced protein kinase 1 and microtubule-associated protein tau. Most recently, heterozygous mutations in LRRK2 (leucine-rich repeat kinase 2) were found to cause late-onset, autosomal-dominant PD. Despite their consistent clinical phenotype, family members with LRRK2 mutations can have variable alpha-synuclein and tau pathologies. Lrrk2 is a member of the Roc (Ras of complex proteins) family, with Ras GTPase and MAPKKK (mitogen-activated protein kinase kinase kinase) catalytic domains. Thus its discovery highlights vesicle dynamics and secondary-messenger signalling in disease pathophysiology. To diagnose a disease accurately and effectively treat it, requires an understanding of its molecular pathogenesis. Herein, we provide an overview of the genetics of PD, how these discoveries are revolutionizing long-held beliefs and more importantly how this knowledge may be translated into patient therapy.
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PMID:Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson's disease. 1604 50

Parkinson's disease (PD) is characterized by a unique clinical constellation that includes: slowness, rigidity, gait difficulty, and tremor at rest. Pathological studies have linked this presentation to the loss of midbrain dopamine neurons (Gelb et al. 1999) although other neuronal populations are also targeted in PD. Epidemiological data implicate both genetic and environmental factors in the etiology of the disease. The identification of a series of genes that underlie relatively rare, familial forms of Parkinsonism (a clinical term that encompasses 'sporadic' PD, familial Parkinson's-like forms, as well as other related syndromes) has brought excitement to the field. Three of the mutated familial Parkinsonism (FP) genes: Parkin, DJ-1, and PINK1, typically present with apparent autosomal recessive inheritance and are implicated in mitochondria and oxidative stress-related survival pathways. Two other FP genes: alpha-Synuclein (alphaSyn) and LRRK2, present in an autosomal dominant pattern and are associated with prominent intracellular protein inclusions. A series of recent publications suggest novel pathways that may link the FP genes.
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PMID:Parkinsonism genes: culprits and clues. 1683 55

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder characterized clinically by bradykinesia, rigidity, tremor, gait dysfunction, and postural instability. Several genes have been identified for monogenic disorders that variably resemble Parkinson's disease. Here, we focus on PARK7, a gene relates to an autosomal recessive form of early-onset Parkinsonism and encodes a protein named DJ-1. Though the exact role of DJ-1 needs to be elucidated, it is generally thought to be functioned as a molecular chaperone and an oxidative sensor (or antioxidative factor). We will review the protective role of DJ-1 to prevent dopaminergic neurons in the substantia nigra pars compacta (SNpc) from degeneration and how its dysfunction would lead to neurodegeneration.
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PMID:The role of DJ-1 in the pathogenesis of Parkinson's disease. 1770 38

Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity. Current medications only provide symptomatic relief and fail to halt the death of dopaminergic neurons. A major hurdle in development of neuroprotective therapies are due to limited understanding of disease processes leading to death of dopaminergic neurons. While the etiology of dopaminergic neuronal demise is elusive, a combination of genetic susceptibilities and environmental factors seems to play a critical role. The majority of PD cases are sporadic however, the discovery of genes linked to rare familial forms of disease (encoding alpha-synuclein, parkin, DJ-1, PINK-1 and LRRK2) and studies from experimental animal models has provided crucial insights into molecular mechanisms in disease pathogenesis and identified probable targets for therapeutic intervention. Recent findings implicate mitochondrial dysfunction, oxidative damage, abnormal protein accumulation and protein phosphorylation as key molecular mechanisms compromising dopamine neuronal function and survival as the underlying cause of pathogenesis in both sporadic and familial PD. In this review we provide an overview of the most relevant findings made by the PD research community in the last year and discuss how these significant findings improved our understanding of events leading to nigrostriatal dopaminergic degeneration, and identification of potential cell survival pathways that could serve as targets for neuroprotective therapies in preventing this disabling neurological illness.
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PMID:Parkinson's disease. 1791 Nov 61

Parkinson's disease (PD) is a neurodegenerative disorder affecting nearly 3 million patients in Europe and North America, characterized by a core phenotype of motor deficits, akinesia, rigidity, postural disturbance and tremor, which is complicated by other neurological deficits during its long progression. Our knowledge about the pathophisiology of PD was limited, up to 25 years ago, to the observation of the lesion of the nigro-striatal dopamine neurons in these patients. The subjects who developed PD as a consequence of exposure to neurotoxic compounds, increased our knowledge about the pathogenesis of this disease. More recently, genetic alterations have been found in patients with PD. The function of the proteins coded by the genes involved in PD has been investigated in genetic models of this disease from invertebrate to rodents. Mutated proteins responsible for PD have been tested in vivo and in vitro, in cellular models or in artificial constructs. A wealth of important information about the function of alpha-synuclein, parkin, DJ-1, PINK and dardarin is available, most notably about the first two causes of familial PD discovered, alpha-synuclein and parkin, responsible for autosomal dominant and autosomal recessive PD, respectively. Different animal models of alpha-synuclein and parkin have been extensively investigated. The in vitro and in vivo studies performed in genetic models of PD have shown that the proteins involved in the pathogenesis of PD interact with one another and have multiple mechanisms of cell toxicity. From the available data, it is clear that the mechanisms leading to cell degeneration in PD are variable in the different subtypes of this disease. Neuroprotective therapies should, therefore, be multiple and tailored according to the factors involved in the different cases. In this study, we review what we have learned from the genetic models of PD and the putative strategies to be tested in the near future.
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PMID:On the pathogenesis and neuroprotective treatment of Parkinson disease: what have we learned from the genetic forms of this disease? 1885 61

Parkinson's disease (PD) is characterized clinically by motor symptoms such as resting tremor, slowness of movement, rigidity, and postural instability, and pathologically by the degeneration of multiple neuronal types, including, most notably, dopaminergic (DA) neurons in the substantia nigra. Current medical treatment for PD focuses on dopamine replacement, but dopamine replacement ultimately fails and has little effect on a variety of dopamine-independent symptoms both within and outside the nervous system. To develop new therapies, we need to aim at alleviating widespread cellular defects in addition to those focusing on DA neuronal survival. Recent observations in Drosophila have provided important insights into the cellular basis of PD pathogenesis through the demonstration that two genes associated with familial forms of PD, pink1 and parkin, function in a common pathway. In this pathway, pink1 functions upstream of parkin to regulate mitochondrial fission/fusion dynamics and normal mitochondrial function. Subsequent observations in both fly and mammalian systems show that these proteins are important for sensing mitochondrial damage and recruiting damaged mitochondria to the quality control machinery for subsequent removal. This chapter reviews these findings, as well as studies of DJ-1 and Omi/HtrA2, two additional genes associated with PD that have also been implicated to regulate mitochondrial function. The chapter ends by discussing how Drosophila can be used to probe further the functions of pink1 and parkin and the regulation of mitochondrial quality more generally. In addition to PD, defects in mitochondrial function are associated with normal aging and with many diseases of aging. Thus, insights gained from the studies of mitochondrial dynamics and quality control in Drosophila are likely to be of general significance.
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PMID:What have we learned from Drosophila models of Parkinson's disease? 2088 67

Parkinson's disease (PD) is the second most common neurodegenerative disorder behind Alzheimer's disease. There are currently no therapies proven to halt or slow the progressive neuronal cell loss in PD. A better understanding of the molecular and cellular causes of PD is needed to develop disease-modifying therapies. PD is an age-dependent disease that causes the progressive death of dopamine-producing neurons in the brain. Loss of substantia nigra dopaminergic neurons results in locomotor symptoms such as slowness of movement, tremor, rigidity and postural instability. Abnormalities in other neurotransmitters, such as serotonin, may also be involved in both the motor and non-motor symptoms of PD. Most cases of PD are sporadic but many families show a Mendelian pattern of inherited Parkinsonism and causative mutations have been identified in genes such as Parkin, DJ-1, PINK1, alpha-synuclein and leucine rich repeat kinase 2 (LRRK2). Although the definitive causes of idiopathic PD remain uncertain, the activity of the antioxidant enzyme glutathione peroxidase 1 (Gpx1) is reduced in PD brains and has been shown to be a key determinant of vulnerability to dopaminergic neuron loss in PD animal models. Furthermore, Gpx1 activity decreases with age in human substantia nigra but not rodent substantia nigra. Therefore, we crossed mice deficient for both Parkin and DJ-1 with mice deficient for Gpx1 to test the hypothesis that loss-of-function mutations in Parkin and DJ-1 cause PD by increasing vulnerability to Gpx1 deficiency. Surprisingly, mice lacking Parkin, DJ-1 and Gpx1 have increased striatal dopamine levels in the absence of nigral cell loss compared to wild type, Gpx1(-/-), and Parkin(-/-)DJ-1(-/-) mutant mice. Additionally, Parkin(-/-)DJ-1(-/-) mice exhibit improved rotarod performance and have increased serotonin in the striatum and hippocampus. Stereological analysis indicated that the increased serotonin levels were not due to increased serotonergic projections. The results of our behavioral, neurochemical and immunohistochemical analyses reveal that PD-linked mutations in Parkin and DJ-1 cause dysregulation of neurotransmitter systems beyond the nigrostriatal dopaminergic circuit and that loss-of-function mutations in Parkin and DJ-1 lead to adaptive changes in dopamine and serotonin especially in the context of Gpx1 deficiency.
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PMID:Surprising behavioral and neurochemical enhancements in mice with combined mutations linked to Parkinson's disease. 2407 52

We present results of homozygosity mapping in two siblings affected with early onset Parkinson's disease (EOPD) and mutation screening of ATP13A2 in these and other Iranian EOPD patients. Genome-wide SNP homozygosity analysis revealed linkage to a locus that included ATP13A2, and sequencing of the gene revealed a novel p.Gln858*-causing mutation in the homozygous state in the siblings. Sequencing of the gene in seven other unrelated EOPD patients previously shown not to have mutations in PRKN, DJ-1, PINK1, and LRRK2 identified the same homozygous p. Gln858*-causing mutation in another patient. Haplotype analysis revealed that two alleles harboring the mutation were not identical by decent. The variation identified represents the 13th known disease causing mutation in ATP13A2. The clinical features of the patients who harbored the mutation are compared to those of previously reported patients with mutations in ATP13A2. Bradykinesia and rigidity, but not tremor, were reported in nearly all the patients. l-dopa administration, though initially effective, usually caused dyskinesia upon prolonged usage. Eye movement abnormalities including saccades and supranuclear gaze palsy, were almost always observed. Dystonia and bulbar anomalies were common but more variable manifestations. Although a degree of cognitive decline was found in most of the patients, the decline was often mild and absent in one patient. Age at onset of symptoms was usually in the second decade of life, and sometimes in the third decade.
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PMID:Identification of p.Gln858* in ATP13A2 in two EOPD patients and presentation of their clinical features. 2494 80

Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The neurodegenerative condition of Parkinson's disease (PD) is the most common cause of parkinsonism. PD is classified as sporadic PD and familial PD. Whereas idiopathic PD is caused by a number of complex factors, familial PD is a result of mutations in PD-associated genes. Unraveling the mechanisms surrounding familial PD will offer pivotal clues in understanding etiology of not only familial PD but also sporadic PD. We have demonstrated neuroprotective effects with particular focus on DJ-1. On the other hand, idiopathic basal ganglia calcification, also known as Fahr disease (FD) is another condition characterized by parkinsonism. In 2012, solute carrier family 20A2 (SLC20A2) was identified as the causative gene for familial FD. Our analysis of patient samples revealed a novel mutation in SLC20A2. Type-III sodium-dependent phosphate transporter 2 (PiT-2), the protein encoded by SLC20A2, plays an important role in phosphate homeostasis. However, PiT-2's role in the pathology of FD remains largely unclear. We have established induced pluripotent stem (iPS) cells from FD patients and are investigating their usefulness in drug development. Here, we present some of our latest research findings.
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PMID:[The causative gene of Parkinsonism and its medical treatment strategy]. 2545 35


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