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)

Two mutations in the gene encoding alpha-synuclein have been linked to early-onset Parkinson's disease (PD). alpha-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain. This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied alpha-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of alpha-synuclein (A53T and A30P) are, like wild-type alpha-synuclein (WT), disordered in dilute solution. However, at higher concentrations, Lewy body-like fibrils and discrete spherical assemblies are formed; most rapidly by A53T. Thus, mutation-induced acceleration of alpha-synuclein fibril formation may contribute to the early onset of familial PD.
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PMID:Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. 980 58

In the last decade, a new degenerative dementia, probably the second most common after Alzheimer's disease (AD), has been increasingly recognized under the consensus name of dementia with Lewy bodies (DLB). This article reviews current clinical, genetic, and pathological DLB data and indicates directions for future research. DLB overlaps in clinical, pathological, and genetic features with AD and Parkinson's disease (PD). Clinically, it is characterized by progressive cognitive impairment with significant fluctuations in alertness, parkinsonism, and psychosis with recurrent hallucinations. The neuropathological hallmarks are the intracytoplasmic inclusions in substantia nigra typical of PD, known as Lewy bodies (LB) but distributed widely throughout paralimbic and neocortical regions. Most of the cases also coexist with a plaque predominant AD. It is probably the unique and differential distribution of the lesions throughout cortical and subcortical structures in each of these disorders that supports a specific clinical syndrome and may ultimately prove most useful in understanding their different etiologies. Several genes have recently been implicated in LB formation. Special interest arises from mutations in the alpha-synuclein gene, which appears to be responsible for autosomal dominant PD in several kindreds. This gene encodes a presynaptic protein, a fragment of which is present in AD plaques. Recent studies show intense and quite specific alpha-synuclein immunoreactivity in LB and related neurites, suggesting a potential role of this protein in the aggregation or precipitation of LB inclusions.
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PMID:Dementia with Lewy bodies. 980 70

Missense mutations in the alpha-synuclein gene cause familial Parkinson's disease (PD), and alpha-synuclein is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease (AD). To determine whether alpha-synuclein is a component of LBs in familial AD (FAD) patients with known mutations in presenilin (n = 65) or amyloid precursor protein (n = 9) genes, studies were conducted with antibodies to alpha-, beta-, and gamma-synuclein. LBs were detected with alpha- but not beta- or gamma-synuclein antibodies in 22% of FAD brains, and alpha-synuclein-positive LBs were most numerous in amygdala where some LBs co-localized with tau-positive neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples contained alpha-synuclein-positive LBs, these inclusions may be more common in FAD brains than previously reported. Furthermore, alpha-synuclein antibodies decorated LB filaments by immunoelectron microscopy, and Western blots revealed that the solubility of alpha-synuclein was reduced compared with control brains. The presence of alpha-synuclein-positive LBs was not associated with any specific FAD mutation. These studies suggest that insoluble alpha-synuclein aggregates into filaments that form LBs in many FAD patients, and we speculate that these inclusions may compromise the function and/or viability of affected neurons in the FAD brain.
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PMID:Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. 981 26

Recent work has shown that abnormal filamentous inclusions within some nerve cells is a characteristic shared by Alzheimer's disease, some frontotemporal dementias, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, as well as Huntington's disease and other trinucleotide repeat disorders. This suggests that in each of these disorders, the affected nerve cells degenerate as a result of these abnormal inclusions. Except for trinucleotide repeat disorders, the filaments involved have been shown to consist of either the microtubule-associated protein tau or alpha-synuclein. Over the past year, mutations in the genes for tau and alpha-synuclein have been identified as the genetic causes of some familial forms of frontotemporal dementia and Parkinson's disease, respectively. The discovery last year of neuronal intranuclear inclusions in Huntington's disease and other disorders with expanded glutamine repeats has suggested a unifying mechanism underlying the pathogenesis of this class of neurodegenerative diseases.
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PMID:Filamentous nerve cell inclusions in neurodegenerative diseases. 981 17

A genetic contribution to the etiology of Parkinson's disease (PD) is now well established, based on the demonstration of a familial aggregation of the disease as demonstrated by several case control and twin studies, and on the description of large multigenerational families, in whom PD is inherited in a Mendelian fashion. In a few families with autosomal dominant inheritance and typical Lewy-body pathology, a gene locus has been mapped to the long arm of chromosome 4, and mutations have been identified in the gene for alpha-synuclein. A gene causing autosomal recessive parkinsonism of juvenile onset has been mapped to chromosome 6, and the causative gene has been identified and named Parkin. This form of parkinsonism differs pathologically from the sporadic disease, as no Lewy bodies are found in the substantia nigra. A third locus, again in families with dominant inheritance, typical Lewy-body pathology and late onset, has been mapped to chromosome 2pl3. At present, there is no evidence that any of these genes for familial Parkinsonian syndromes have a direct role in the etiology of the common sporadic form of PD. However, the elucidation of the molecular sequence of events leading to nigral degeneration in these inherited cases is likely to shed light on the molecular pathogenesis of this common neurodegenerative disorder.
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PMID:Genetics of Parkinson's disease. 983 35

Alpha-synuclein (alpha-syn) protein has been found in association with the pathological lesions of a number of neurodegenerative diseases. Recently, mutations in the alpha-syn gene have been reported in families susceptible to an inherited form of Parkinson's disease. We report here that human wild-type alpha-syn, PD-linked mutant alpha-syn(Ala30Pro) and mutant alpha-syn(Ala53Thr) proteins can self-aggregate and form amyloid-like filaments. The mutant alpha-syn forms more beta-sheet and mature filaments than the wild-type protein. These findings suggest that accumulation of alpha-syn as insoluble deposits of amyloid may play a major role in the pathogenesis of these neurodegenerative diseases.
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PMID:Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of alpha-synuclein protein implicated in Parkinson's disease. 986 27

Alpha-synuclein (alpha-syn) protein and a fragment of it, called NAC, have been found in association with the pathological lesions of a number of neurodegenerative diseases. Recently, mutations in the alpha-syn gene have been reported in families susceptible to an inherited form of Parkinson's disease. We have shown that human wild-type alpha-syn, mutant alpha-syn(Ala30Pro) and mutant alpha-syn(Ala53Thr) proteins can self-aggregate and form amyloid-like filaments. Here we report that aggregates of NAC and alpha-syn proteins induced apoptotic cell death in human neuroblastoma SH-SY5Y cells. These findings indicate that accumulation of alpha-syn and its degradation products may play a major role in the development of the pathogenesis of these neurodegenerative diseases.
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PMID:Aggregates from mutant and wild-type alpha-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of beta-sheet and amyloid-like filaments. 986 28

Recently it has been reported that a missense G(88)C mutation within exon 3 and a missense G(209)A mutation within exon 4 of the alpha-synuclein gene were linked to familial Parkinson's Disease (PD). We decided to investigate if these and any other mutations in exons 3 and 4 of the alpha-synuclein gene could be detected in sixty two sporadic PD and dementia with Lewy bodies (DLB) patients. Four cases of familial DLB were also studied, two of which were from the same family. Single stranded conformational polymorphism, DNA sequencing analyses and PCR-RFLP of exons 3 and 4 failed to reveal any nucleotide changes. However, three nucleotide differences occurred in the intron 4 sequence compared to the published sequence. This study adds further support to the idea that these particular mutation in the alpha-synuclein gene are a rare case of PD and now, as we have shown here, also of DLB.
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PMID:Mutation screening in exons 3 and 4 of alpha-synuclein in sporadic Parkinson's and sporadic and familial dementia with Lewy bodies cases. 987 30

A specific mutation (A53T) in the encoding region for alpha-synuclein has been identified in a large multigenerational family with an autosomal dominant parkinsonism known as the Contursi kindred. In this study, we used a monoclonal antibody directed against alpha-synuclein in order to identify novel proteins in the brain of an affected member of this kindred who had come to autopsy. Homogenates from the frontal cortex and caudate nucleus were examined using Western blot techniques and compared to matched autopsy specimens from control subjects and patients with various forms of parkinsonism. Western blots, using a 15-min exposure time, revealed the expected 19-kDa band representing alpha-synuclein in all brain samples examined. However, a novel band in the 36-kDa range was also present in the Contursi brain which was not seen in cortex or caudate from control brains or in frontal cortex from 14 cases of typical Parkinson's disease. With a 24-h exposure time, this band was faintly seen in the caudate nucleus of three of the Parkinson's disease cases. Surprisingly, the 36-kDa band (as well as other high-molecular-weight bands) was also present in frontal cortex and caudate nucleus in 3 additional cases that met diagnostic criteria for both Parkinson's disease and Alzheimer's disease. A preliminary analysis of samples from the frontal cortex of 10 Alzheimer's disease cases revealed a 36-kDa band in only one instance. The identification of novel alpha-synuclein-immunoreactive bands in these various forms of parkinsonism may open new research avenues for exploring the relationship between abnormal protein deposition in the brain and one or more neurodegenerative disorders, including the Contursi form of familial parkinsonism.
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PMID:Novel alpha-synuclein-immunoreactive proteins in brain samples from the Contursi kindred, Parkinson's, and Alzheimer's disease. 987 3

Parkinson's disease (PD) is one of the most frequent neurodegenerative disorders. The role of genetic factors in its pathogenesis is supported by several lines of evidence: the high concordance in twins using PET scan; the increased risk among relatives of PD patients in case control and family studies; the existence of monogenic forms of PD. the alpha-synuclein gene is involved in a rare dominant form of the disease for which a new locus has been recently mapped to chromosome 2. Early onset autosomal recessive parkinsonism, which maps to chromosome 6q, appears to be frequent in Japan and in Europe. The genes for several monogenic forms of this entity should be identified soon, providing new insight into the pathophysiology of the disease. However, it is not clear if these genes will be relevant to apparently sporadic cases. In the long term, genotyping of affected sib-pairs should permit localisation and identification of other genetic susceptibility factors. These complementary approaches will contribute to the elucidation of the mechanism of PD and should provide new targets for drug therapies.
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PMID:[Parkinson disease: monogenic forms and genetic susceptibility factors]. 988 26


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