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 alpha-synuclein, parkin and ubiquitin C-terminal hydrolase L1, and defects in 26/20S proteasomes, cause or are associated with the development of familial and sporadic Parkinson's disease (PD). This suggests that failure of the ubiquitin-proteasome system (UPS) to degrade abnormal proteins may underlie nigral degeneration and Lewy body formation that occur in PD. To explore this concept, we studied the effects of lactacystin-mediated inhibition of 26/20S proteasomal function and ubiquitin aldehyde (UbA)-induced impairment of ubiquitin C-terminal hydrolase (UCH) activity in fetal rat ventral mesencephalic cultures. We demonstrate that both lactacystin and UbA caused concentration-dependent and preferential degeneration of dopaminergic neurons. Inhibition of 26/20S proteasomal function was accompanied by the accumulation of alpha-synuclein and ubiquitin, and the formation of inclusions that were immunoreactive for these proteins, in the cytoplasm of VM neurons. Inhibition of UCH was associated with a loss of ubiquitin immunoreactivity in the cytoplasm of VM neurons, but there was a marked and localized increase in alpha-synuclein staining which may represent the formation of inclusions bodies in VM neurons. These findings provide direct evidence that impaired protein clearance can induce dopaminergic cell death and the formation of proteinaceous inclusion bodies in VM neurons. This study supports the concept that defects in the UPS may underlie nigral pathology in familial and sporadic forms of PD.
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PMID:Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. 1206 77

Although originally discounted, hereditary factors have emerged as the focus of research in Parkinson's disease (PD). Genetic studies have identified mutations in alpha-synuclein and ubiquitin C-terminal hydrolase as rare causes of autosomal dominant PD and mutations in parkin as a cause of autosomal recessive PD. Functional characterization of the identified disease genes implicates the ubiquitin-mediated protein degradation pathway in these hereditary forms of PD and also in the more common sporadic forms of PD. Subsequent identification of further loci in familial PD and diverse genetic factors modulating the risk for sporadic PD point to substantial genetic heterogeneity in the disease. Thus, new candidate genes are expected to encode proteins either involved in ubiquitin-mediated protein degradation or sequestrated in intracytoplasmic protein aggregations. Future identification of disease genes is required to confirm this hypothesis, thereby unifying the clinical and genetic heterogeneity of PD, including the common sporadic form of the disease, by one biochemical pathway.
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PMID:Parkinson's disease: one biochemical pathway to fit all genes? 1206 34

Parkinson's disease was thought, until recently, to have little or no genetic component. This notion has changed with the identification of three genes, and the mapping of five others, that are linked to rare familial forms of the disease (FPD). The products of the identified genes, alpha-synuclein (PARK 1), parkin (PARK 2), and ubiquitin-C-hydrolase-L1 (PARK 5) are the subject of intense cell-biological and biochemical studies designed to elucidate the underlying mechanism of FPD pathogenesis. In addition, the complex genetics of idiopathic PD is beginning to be unraveled. Genetic information may prove to be useful in identifying new therapeutic targets and identifying the preclinical phase of PD, allowing treatment to begin sooner.
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PMID:Genetics of Parkinson's disease and biochemical studies of implicated gene products. 1207 73

Parkinson's disease is a neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic nigrostriatal pathway, and the presence of Lewy bodies. Over the past few years, several genes involved in inherited forms of the disease have been uncovered. In a small number of families with autosomal dominant inheritance, mutations have been identified in the genes encoding a-synuclein and ubiquitin carboxy-terminal hydrolase L1. Mutations in the parkin gene are a common cause of autosomal recessive parkinsonism with early onset, and also account for more than 15% of isolated cases with onset before age 45. The function of Parkin, a ubiquitin ligase involved in the degradation of protein substrates by the ubiquitin-proteasome pathway, highlights that ubiquitin-mediated proteolysis may play an important role in the pathophysiology of idiopathic Parkinson's disease.
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PMID:[Parkin, alpha-synuclein and other molecular aspects of Parkinson's disease]. 1213 40

MPTP burst upon the medical landscape two decades ago, first as a mysterious parkinsonian epidemic, triggering an unparalleled quest for the toxin's identity, and closely followed by an intense pursuit of its cellular mechanisms of action. MPTP treatment created an animal model of many features of Parkinson's disease (PD), used primarily in primates and later in mice. The critical role of oxidative stress damage to vulnerable dopamine neurons, as well as for neurodegenerative diseases in general, emerged from MPTP neurotoxicity. A remarkable cross-fertilization of basic and clinical findings, including genetic and epidemiologic studies, has greatly advanced our understanding of PD and revealed multiple factors contributing to the parkinsonian phenotypes. Brain imaging localizes sites of action and provides potential presymptomatic diagnostic testing. Epidemiologic reports linking PD with pesticide exposure were complimented by supportive evidence from biochemical studies of MPTP and structurally related compounds, especially after low-level, long-term exposure. Genetic studies on the role of risk genes, such as alpha-synuclein or parkin, have been validated by biochemical, anatomical and neurochemical investigations showing factors interacting to produce pathophysiology in the animal model. Focusing on the pivotal role of mitochondria, subcellular pathways participating in cell death have been clarified by unraveling similar sites of action of MPTP. Along the way, compounds antagonizing or potentiating MPTP effects indicated new PD therapies, some of the former achieving clinical trials. The future is encouraging for combating PD and will continue to benefit from the MPTP neurotoxicity model.
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PMID:MPTP: insights into parkinsonian neurodegeneration. 1220 Jan 92

Parkinson's disease (PD) was noted to have a familial component as early as 1880 (Leroux, 1880). More recently, the discovery of several genetic factors influencing parkinsonism has emphasized the importance of heredity in PD. The clinical spectrum of familial parkinsonism is wide; it includes not only PD, but also dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), essential tremor, and other disorders. In the general population, it is likely that PD results from combined genetic and environmental factors, most of which are not yet known. The discovery of causal mutations in the gene for alpha-synuclein, parkin, and of genetic linkages to chromosomes 2p4, 4p5, and three loci on 1q6-8 have revolutionized PD research. This review focuses on recent progress in the Mendelian genetics of PD and those diseases in which parkinsonism is a prominent feature, and considers how these discoveries modify our beliefs regarding the etiology and pathogenesis of these disorders.
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PMID:Genetics of parkinsonism. 1221 Aug 52

We report on clinical (18)F-labeled 6-fluorodopa ((18)F-dopa) positron emission tomography (PET) and molecular genetic analyses of an ethnic Chinese family in which three siblings presented with early-onset Parkinson's disease. As described in some parkin patients, neither sleep benefit nor diurnal fluctuation was noted. Interestingly, depression, anxiety, and obsessive-compulsive disorders were manifest. The (18)F-dopa PET scans showed bilateral presynaptic dopaminergic dysfunction without marked lateralization. Molecular genetic analysis showed identical chromosome 6 haplotypes inherited by affected subjects, with alternate allelic deletions of parkin exons 3 and 4. Furthermore, mRNA analyses identified aberrantly spliced parkin transcripts, suggesting that unusual parkin protein isoforms may be expressed in the brain and retain some function.
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PMID:Clinical, 18F-dopa PET, and genetic analysis of an ethnic Chinese kindred with early-onset parkinsonism and parkin gene mutations. 1221 Aug 55

Parkinson's disease is a complex disorder in which the genetic aspects are only just being realized. The underlying cause for the degeneration of dopaminergic substantia nigra neurons and the formation of Lewy bodies in Parkinson's disease is unknown. The identification of clear inherited forms of the disease has provided important clues as to how this complex process may be occurring. Mutations have now been identified in the alpha-synuclein (4q21.3-23), parkin (6q25.2-27), and ubiquitin carboxy terminal hydrolase-L1 (4p16.3) genes in families with Parkinson's disease. Four additional chromosomal locations; 2p13, 4p14-15, 1p35-36, and 12p11.2-q13.1 have been linked to Parkinson's disease families but no pathologic gene mutations have been identified to date. As additional Parkinson's disease loci are mapped and their genes identified we will continue to add to our understating of the critical biochemical pathways involved and be able to develop effective disease altering treatments.
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PMID:Parkinson's genetics--creating exciting new insights. 1221 36

Two mutations in the alpha-synuclein gene and various mutations in the parkin gene are associated with familial Parkinson's disease (PD). The present study was performed to analyse if mutations in these genes could be detected in Finnish patients with familial PD. The subjects comprised 22 unrelated patients with familial PD. The molecular genetic analysis consisted of sequence analysis of the non-coding and coding exons of the alpha-synuclein gene and screening of eight point mutations in the parkin gene. In addition, a total of 67 controls and 45 patients with sporadic PD were included in the association analysis on polymorphism of the alpha-synuclein gene. Screened point mutations in the parkin gene were not detected. Sequencing of the coding exons 2-6 of the alpha-synuclein gene did not reveal any mutations or polymorphisms. However, three novel alterations in the T10A7 sequence at the 5' end of the non-coding exon 1' of the alpha-synuclein gene were found. The frequencies of the exon 1' polymorphic genotypes or alleles between familial PD patients and control subjects revealed no statistically significant differences. No association for sporadic PD was observed. The results do not support a role for the alpha-synuclein gene or point mutations of the parkin gene in familial PD in our sample.
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PMID:Molecular genetic analysis of the alpha-synuclein and the parkin gene in Parkinson's disease in Finland. 1222 Mar 78

Parkinson's disease was thought, until recently, to have little or no genetic component. This notion has changed with the identification of three genes, and the mapping of five others, that are linked to rare familial forms of the disease (FPD). The products of the identified genes, alpha-synuclein (PARK 1), parkin (PARK 2), and ubiquitin-C-hydrolase-L1 (PARK 5) are the subject of intense cell-biological and biochemical studies designed to elucidate the underlying mechanism of FPD pathogenesis. In addition, the complex genetics of idiopathic PD is beginning to be unraveled. Genetic information may prove to be useful in identifying new therapeutic targets and identifying the preclinical phase of PD, allowing treatment to begin sooner.
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PMID:Genetics of Parkinson's disease and biochemical studies of implicated gene products. 1223 62


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