Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Silver techniques for intraneuronal cytoskeleton abnormalities (neurofibrillary tangles and neuropil threads) and extracellular A4-amyloid deposits were used to examine lesions of the cerebral cortex in six cases of progressive supranuclear palsy (three were mentally unimpaired and three showed moderate degrees of dementia). Deposits of A4-amyloid protein occurred in small numbers or were absent. Neurofibrillary tangles and neuropil threads were present in all cases and were largely confined to the allocortex. A characteristic pattern of changes was found in the entorhinal cortex. The three mentally unimpaired individuals had mild cortical changes virtually confined to the transentorhinal region while all of the demented patients showed severe destruction of the superficial cellular layer in both the transentorhinal and entorhinal region. This pattern of allocortical destruction closely resembles that seen in clinically incipient Alzheimer's disease or in mentally impaired cases of Parkinson's disease. The entorhinal region receives dense input from isocortical association areas and projects via the perforant path to the hippocampal formation. The cells of origin of major portions of the perforant path are located within the superficial entorhinal cellular layer. Destruction of this layer partially or totally disconnects the hippocampus from the isocortex. The specific pattern of entorhinal destruction is considered to contribute to cognitive impairment and personality changes, frequently seen in patients with progressive supranuclear palsy.
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PMID:Allocortical neurofibrillary changes in progressive supranuclear palsy. 146 62

Phosphatidylinositol 4-kinase (PI 4-kinase) and phosphatidylinositol 4-phosphate kinase (PIP kinase) were assayed in membranes prepared from samples of human frontal cortex initially frozen at autopsy. PI 4-kinase activity was significantly lower in Alzheimer's disease patients relative to age-matched controls or patients with Parkinson's disease. PIP kinase was not different in Alzheimer's versus age-matched controls. The beta amyloid protein fragment 1-40 inhibited PI 4-kinase activity in assays of control human or rat cortical membranes. Fragments 1-28 and 25-35 could not mimic the effects of fragment 1-40 while a reverse peptide 40-1 was equipotent. The inhibition of PI 4-kinase by fragment 1-40 was competitive with substrate. The beta amyloid protein fragments had diverse effects on phosphoinositide-specific phospholipase C (PI-PLC) as assayed in rat cortical membranes. Low concentrations of fragment 1-40 stimulated, while high concentrations of 1-40 or 40-1 inhibited PI-PLC activity. Fragment 25-35 stimulated PI-PLC nearly 3-fold, while fragment 1-28 had only minor effects on the enzyme. The results suggest alterations in phosphoinositide metabolism in Alzheimer's disease which could affect signal transduction and/or cytoskeletal organization.
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PMID:Effects of Alzheimer's disease-related beta amyloid protein fragments on enzymes metabolizing phosphoinositides in brain. 798 26

The heroin analogue 1-methyl-4-phenylpyridinium, MPP(+), both in vitro and in vivo, produces death of dopaminergic substantia nigral cells by inhibiting the mitochondrial NADH dehydrogenase multienzyme complex, producing a syndrome indistinguishable from Parkinson's disease. Similarly, a fragment of amyloid protein, Abeta(1-42), is lethal to hippocampal cells, producing recent memory deficits characteristic of Alzheimer's disease. Here we show that addition of 4 mM d-beta-hydroxybutyrate protected cultured mesencephalic neurons from MPP(+) toxicity and hippocampal neurons from Abeta(1-42) toxicity. Our previous work in heart showed that ketone bodies, normal metabolites, can correct defects in mitochondrial energy generation. The ability of ketone bodies to protect neurons in culture suggests that defects in mitochondrial energy generation contribute to the pathophysiology of both brain diseases. These findings further suggest that ketone bodies may play a therapeutic role in these most common forms of human neurodegeneration.
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PMID:D-beta-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. 1080

Cerebrospinal fluid (CSF) levels of tau, beta-amyloid(1-42) and growth-associated protein 43 (GAP-43) were studied in patients with frontotemporal dementia (FTD; n = 17), Alzheimer's disease (AD; n = 60), subcortical white-matter dementia (SWD; n = 24), Parkinson's disease (PD; n = 23) and dysthymia (n = 19) and in age-matched controls (n = 32). CSF-tau was significantly increased only in AD, and CSF-beta-amyloid(1-42) was significantly decreased in AD and SWD as compared to controls, and in AD compared to FTD. CSF-GAP-43 was significantly decreased only in PD. The GAP-43/tau ratio was decreased in all the patient groups except the dysthymia group compared to controls. A positive correlation was found between CSF-GAP-43 and CSF-tau in all groups. The results suggest normal levels of CSF-tau and CSF-beta-amyloid(1-42) in FTD, which will aid in the clinical separation of FTD from AD. In SWD, decreased levels of CSF-beta-amyloid(1-42) suggest concomitant involvement of vascular and amyloid protein mechanisms.
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PMID:CSF levels of tau, beta-amyloid(1-42) and GAP-43 in frontotemporal dementia, other types of dementia and normal aging. 1107 52

It is now well accepted that inflammatory events contribute to the pathogenesis of numerous neurological disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease, and AID's dementia. Whereas inflammation in the periphery is subject to rapid down regulation by increases in anti-inflammatory molecules and the presence of scavenging soluble cytokine receptors, the presence of an intact blood-brain barrier may limit a similar autoregulation from occurring in brain. Mechanisms intrinsic to the brain may provide additional immunomodulatory functions, and whose dysregulation could contribute to increased inflammation in disease. The findings that noradrenaline (NA) reduces cytokine expression in microglial, astroglial, and brain endothelial cells in vitro, and that modification of the noradrenergic signaling system occurs in some brain diseases having an inflammatory component, suggests that NA could act as an endogenous immunomodulator in brain. Furthermore, accumulating studies indicate that modification of the noradrenergic signaling system occurs in some neurodiseases. In this article, we will briefly review the evidence that NA can modulate inflammatory gene expression in vitro, summarize data supporting a similar immunomodulatory role in brain, and present recent data implicating a role for NA in attenuating the cortical inflammatory response to beta amyloid protein.
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PMID:Noradrenergic regulation of inflammatory gene expression in brain. 1217 79

Alzheimer's disease(AD) is the most common form of neurodegenerative diseases that causes intellectual dysfunction. AD is a genetically heterogenous disorder. Over 100 mutations have been identified in three causative genes, i.e. amyloid protein precursor(APP), presenilin 1(PS1) and presenilin 2(PS2) genes, for early-onset autosomal dominant familial AD(FAD). Apolipoprotein E(APOE) gene has been identified as susceptibility gene for late-onset FAD. The missense mutations in the causative genes lead to abnormal APP processing with overproduction of total A beta protein or A beta 42(43) isoform. The epsilon 4 allele of APOE gene is a genetic risk factor for sporadic AD as well as FAD. Parkinson's disease(PD) is another common form of neurodegenerative disease that causes movement dysfunction. Three genes, i.e. alpha-synuclein (SNCA), parkin(PARK2), and ubiquitin carboxy-terminal hydrolase L1(UCHL1) genes, have been identified as causative genes for familial PD. The B mutation of CYP2D6 gene(CYP2D6*4 allele) is a genetic risk factor for PD. Lewy body(LB), that is an intracellular inclusion body characteristic of PD, is widely distributed in the cerebral cortex of 20 to 30% of AD patients. This disease entity is called as Lewy body variant(LBV) of AD. LBV shares the genetic risk factor with AD and PD, i.e. APOE epsilon 4 allele and CYP2D6 B mutation. Gene diagnosis is possible for familial AD and PD. APOE and CYP2D6 genotyping is also applicable to the future prediction of AD and PD, respectively.
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PMID:[Gene diagnosis of Alzheimer's disease and Parkinson's disease]. 1245 76

The anti-Parkinson drug, rasagiline, a irreversible propargyl possessing monoamine oxidase B inhibitor can protect neurons in vitro and in vivo from a variety of neurotoxic insults including SIN-1, glutamate, the parkinsonism inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, N-methyl-(R)-salsolinol and including beta amyloid protein. Recent studies have shown that rasagiline rapidly modulates intracellular signaling pathways involved in cell survival and death. Specifically rasagiline activates Bcl-2, Bcl-xl, protein kinase C (PKC) and reduces Bax in a variety of cells including PC-12 and neuroblastoma human dopamine derived SH-SY5Y cells. These enzymes play key roles in cellular events including modulation of apoptotic processes, neuronal plasticity and amyloid precursor protein processing. This pharmacological action of rasagiline is also associated with the prevention of the neurotoxin induced fall in mitochondrial membrane potential, opening of mitochondria permeability transition pore, activation of proteasome-ubiquitin complex, inhibition of cytochrome c release and prevention of caspase 3 activation, similar to the actions of cyclosporin A or Bcl-2 over expression in SH-SY5Y cells. Rasagiline and its various derivatives induces PKC dependent release of soluble amyloid precursor protein alpha and which is blocked by inhibitors of alpha-secretase, PKC and MAPK-dependent signaling. Structure-activity relationship with various propargyl containing derivatives of rasagiline including propargylamine itself has shown that the above described pharmacological action of these compounds resides in the propargylamine moiety. These results have provided a new understanding into the mechanism of neuroprotective actions of rasagiline and its anti-Alzheimer drug derivatives TV3326 and TV3279, which are relevant for therapy of Parkinson's disease, Alzheimer's disease and other neurodegenerative diseases.
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PMID:The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. 1455 44

We have used quantitative 2D gel electrophoresis to analyze serum proteins from 422 patients with neurodegenerative diseases and normal individuals in an unbiased approach to identify biomarkers. Differences in abnormal serum levels were found between amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and related disorders for 34 protein biomarker spots, nine of which were related to the complement system. Of these nine, four spots originated from the Complement C3b-alpha-chain (C3c(1), C3c(2a), C3c(2b), and C3dg). The C3c spots (C3c(1), C3c(2a), and C3c(2b)) had the same amino acid sequence and glycosylation, though only C3c(1) was phosphorylated. In addition, Complement Factors H, Bb, and Pre-Serum amyloid protein displayed different serum concentrations in ALS, PD, and normal sera, whereas Complement C4b gamma-chain and Complement Factor I did not. The differential expression of the complement proteins provides potentially useful biomarkers as well as evidence for the involvement of inflammatory processes in the pathogenesis of ALS and PD.
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PMID:Complement C3c and related protein biomarkers in amyotrophic lateral sclerosis and Parkinson's disease. 1651 57

Numerous evidences indicate that the phenotype of a neurodegenerative disease and its pathogenetic mechanism are only loosely linked. The phenotype is directly related to the topography of the lesions and is reproduced whatever the mechanism as soon as the same neurons are destroyed or deficient: the symptoms of Parkinson disease are mimicked by any destruction of the neurons of the substantia nigra, caused for instance by the toxin MPTP. This does not mean that idiopathic Parkinson disease is due to MPTP. In the same way, mouse lines such as Reeler, Weaver and Staggerer in which ataxia occurs spontaneously does not help to understand human ataxias: now that mutations responsible for these phenotypes have been identified, it appears that one is responsible for lissencephaly (mutation of the reelin gene) and the other two have no equivalent in man. Therapeutic attempts, however, rely on the understanding of the pathogenetic mechanisms. Introducing a mutated human transgene in the genome of an animal has, in many instances, significantly improved this understanding. Transgenic mice have proven useful in reproducing lesions seen in neurodegenerative disease such as the plaques of Alzheimer disease (in the APP mouse which has integrated the mutated gene of the amyloid protein precursor), the tau glial and neuronal accumulation (seen in cases of frontotemporal dementias due to tau mutation), the nuclear inclusions caused by CAG triplet expansion (seen in the mutation of Huntington disease and autosomal dominant spinocerebellar ataxias). These recent advances have fostered numerous therapeutic attempts. Transgenesis in drosophila and in the worm Caenorhabditis elegans have opened new possibilities in the screening of protein partners, modifier genes, and potential therapeutic molecules. However, it is also becoming clear that introducing a human mutated gene in an animal does not necessarily trigger pathogenetic cascades identical to those seen in the human disease. Human diseases have to be studied in parallel with their animal models to ensure that the model mimic at least a few original mechanisms, on which new therapeutics may be tested.
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PMID:[Animal models of neurodegenerative diseases]. 1729 28

Interest in amyloidogenesis has exploded in recent years, as scientists recognize the role of amyloid protein aggregates in degenerative diseases such as Alzheimer's and Parkinson's disease. Assembly of proteins or peptides into mature amyloid fibrils is a multistep process initiated by conformational changes, during which intermediate aggregation states such as oligomers, protofibrils, and filaments are sampled. Although once it was assumed that the mature fibril was the biologically toxic species, more recently it has been widely speculated that soluble intermediates are the most damaging. Because of its relevance to mechanism of disease, the paths traversed during fibrillogenesis, and the kinetics of the process, are of considerable interest. In this review we discuss various kinetic models used to describe amyloidogenesis. Although significant advances have been made, construction of rigorous, detailed, and experimentally validated quantitative models remains a work in progress. We briefly review recent literature that illustrates the interplay between kinetics and amyloid-membrane interactions: how do different intermediates interact with lipid bilayers, and how does the lipid bilayer affect kinetics of amyloidogenesis?
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PMID:Kinetics of amyloid formation and membrane interaction with amyloidogenic proteins. 1729 51


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