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)

The term synucleinopathies is used to name a group of neurodegenerative disorders characterized by fibrillary aggregates of alpha-synuclein protein in the cytoplasm of selective populations of neurons and glia. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and multiple system atrophy (MSA). Clinically, they are characterized by a chronic and progressive decline in motor, cognitive, behavioural, and autonomic functions, depending on the distribution of the lesions. Because of clinical overlap, differential diagnosis is sometimes very difficult. Parkinsonism is the predominant symptom of PD, but it can be indistinguishable from the parkinsonism of DLB and MSA. Autonomic dysfunction, which is an isolated finding in PAF, may be present in PD and DLB, but is usually more prominent and appears earlier in MSA. DLB could be the same disease as PD but with widespread cortical pathological states, leading to dementia, fluctuating cognition, and the characteristic visual hallucinations. The deposition of aggregates of synuclein in neurons and glia suggests that a common pathogenic mechanism may exist for these disorders. Even though synuclein may play an important role in disease development in these disorders, in light of the different symptom complex and prognosis and management issues that characterize each disorder, we think that the term synucleinopathy has little practical value as a diagnostic term for the clinician. Clinicians should attempt to reach standard clinical diagnosis on patients, such as PD, PAF, or MSA.
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PMID:Clinical overview of the synucleinopathies. 1450 52

Genetic analysis is changing our view of Parkinson's disease: not only is it challenging the long-cherished views about the diagnosis of the disease, it is also starting to suggest a biochemical pathway to disease pathogenesis. These developments are reviewed in the context of three known (synuclein, parkin, and DJ-1) and one suspected (ubiquitin hydrolase) genes for the disease.
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PMID:Impact of genetic analysis on Parkinson's disease research. 1450 62

Alpha-synuclein has an important role in the pathogenesis of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), comprising a new disease concept, that of alpha-synucleinopathies. Cerebellar degeneration with Purkinje cell depletion is present in the majority of MSA cases. By contrast, cerebellar pathology has not been demonstrated unequivocally in either PD or DLB. Recent immunohistochemical studies using anti-alpha-synuclein antibodies have shown that LB-type degeneration in PD and DLB is more widespread than previously recognized. To determine whether cerebellar Purkinje cells might be involved in alpha-synuclein pathology, we carried out immunohistochemical examinations of the cerebella of patients with PD (n = 10), DLB (n = 7), MSA (n = 10), Alzheimer disease and other tauopathies (n = 9), and age-matched control subjects (n = 10), using antibodies specific for alpha-synuclein. Although no abnormal accumulation of alpha-synuclein was noted in the Purkinje cell somata, numerous alpha-synuclein-positive, round inclusions were found in the cerebellar white matter in all the patients with PD and DLB. Immunohistochemical and ultrastructural examinations revealed that the majority of these inclusions was located in the Purkinje cell axons and consisted of granulo-filamentous structures. No such inclusions were observed in MSA, tauopathies, or controls. These findings indicate that Purkinje cells are also the victims of a-synuclein pathology in PD and DLB, but not in MSA.
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PMID:Alpha-synuclein accumulates in Purkinje cells in Lewy body disease but not in multiple system atrophy. 1450 37

Olfactory dysfunction increases with disease severity in Alzheimer's disease (AD), is early and independent of disease severity in Parkinson's disease (PD), but is absent in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Previous histopathologic studies of olfactory bulbs in AD have shown neurofibrillary tangles (NFTs) and senile plaques while Lewy bodies (LBs) have been described in PD. Little is known about olfactory bulb pathology in PSP and CBD. Tau and alpha-synuclein pathology was assessed with immunohistochemistry in olfactory bulbs of AD (N=15), Lewy body disease (LBD; N=10), LBD with concurrent AD (AD/LBD; N=19), PSP (N=27), CBD (N=3) and cases with no significant neurodegenerative pathology (NSP; N=15). The Braak NFT stage, counts of senile plaques and NFT in cortical and hippocampal sections, and counts of LBs in amygdala and cortical sections were recorded for each case. Apolipoprotein E (APOE) genotypes were determined on DNA prepared from frozen brain tissue. All AD and AD/LBD cases and nine of 10 LBD cases had tau pathology in the anterior olfactory nucleus (AON), but it was uncommon in PSP (9/27), CBD (0/3) and NSP (5/15). Multiple linear regression analysis demonstrated that tau pathology in the AON correlated with Braak stage (P<0.001), cortical LB counts (P<0.001), as well as APOE epsilon4. Tau pathology is common in the olfactory bulb of AD and LBD but is minimal or absent in PSP and CBD. It correlates with APOE epsilon4, severity of tau pathology in the brain and surprisingly with cortical and amygdala LBs, suggesting a possible synergistic effect between tau and synuclein in the AON in cases with both pathologic processes.
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PMID:Tau pathology in the olfactory bulb correlates with Braak stage, Lewy body pathology and apolipoprotein epsilon4. 1450 42

The discovery of two missense mutations in alpha-synuclein gene and the identification of the alpha-synuclein as the major component of Lewy bodies and Lewy neurites have imparted a new direction in understanding Parkinson's disease. Now that alpha-synuclein has been implicated in several neurodegenerative disorders makes it increasingly clear that aggregation of alpha-synuclein is a hallmark feature in neurodegeneration. Although little has been learned about its normal function, alpha-synuclein appears to be associated with membrane phospholipids and may therefore participate in a number of cell signaling pathways. Here, we review the localization, structure, and function of alpha-synuclein and provide a new hypothesis on, (a) the disruption in the membrane binding ability of synuclein which may be the major culprit leading to the alpha-synuclein aggregation and (b) the complexity associated with nuclear localization of alpha-synuclein and its possible binding property to DNA. Further, we postulated the three possible mechanisms of synuclein induced neuronal degeneration in Parkinson's disease.
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PMID:Challenges and complexities of alpha-synuclein toxicity: new postulates in unfolding the mystery associated with Parkinson's disease. 1452 88

Traumatic brain injury (TBI) is one of the most devastating diseases in our society, accounting for a high percentage of mortality and disability. A major consequence of TBI is the rapid and long-term accumulation of proteins. This process largely reflects the interruption of axonal transport as a result of extensive axonal injury. Although many proteins are found accumulating after TBI, three have received particular attention; beta-amyloid precursor protein and its proteolytic products, amyloid-beta (Abeta) peptides, neurofilament proteins, and synuclein proteins. Massive coaccumulations of all of these proteins are found in damaged axons throughout the white matter after TBI. Additionally, these proteins form aggregates in other neuronal compartments and in brain parenchyma after brain trauma. Interestingly, TBI is also an epigenetic risk factor for developing neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Here, the similarities and differences of these accumulations with pathologies of neurodegenerative diseases will be explored. In addition, the potential deleterious roles of protein accumulations on functional outcome and progressive neurodegeneration following TBI will be examined.
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PMID:Protein accumulation in traumatic brain injury. 1452 53

The Lewy body, an eosinophilic inclusion around 10 microns in diameter, is localised in the neuronal perikaryon. Its dense core is surrounded by a clear halo, which is lacking in the so-called "cortical Lewy bodies". Numerous proteins have been identified in Lewy bodies, among which the three neurofilament isoforms, ubiquitin and proteasome subunits. More recently, alpha-synuclein--a pre-synaptic protein--has been found to be the essential constituent of the Lewy body. Alpha-synuclein antibody has greatly increased the sensitivity of the neuropathological examination: it has emphasized the frequency of "Lewy neurites" (accumulation of alpha--synuclein in neuronal processes) and has shown the importance of extra-nigral pathology. Lewy bodies and neurites are indeed to be found in many areas of the central and peripheral nervous system: stellate ganglia, cardiac and enteric plexus, pigmented nuclei of the brainstem, basal nucleus of Meynert, amygdala, limbic nuclei of the thalamus, parahippocampal and cingulate gyri, insula and isocortex. Lewy body diseases include at least three clinical syndromes: 1) idiopathic Parkinson disease in which the brainstem bears the brunt of the pathology 2) Parkinson disease dementia in which Lewy lesions are found in the brainstem and are also abundant in the isocortex. A large number of senile plaques is frequently associated. 3) In dementia with Lewy bodies, the same lesions are observed but the cognitive deficit occurs first or shortly (less than one year) after the motor symptoms.
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PMID:[Lewy bodies, a misleading marker for Parkinson's disease?]. 1455 41

Parkinson's disease (PD) and Alzheimer's (AD) are major progressive neurological disorders, the risk of which increases with advancing age (65 years and over). In familial cases, however, early onset of disease (about 35 years) is observed. In spite of extensive basic and clinical research on PD and AD, no preventive or long-term effective treatment strategies are available. Several studies have indicated that oxidative stress is a major risk factor for the initiation and progression of sporadic PD and AD. Even a-synuclein and b-amyloid fragments that are associated with the PD and AD, respectively, mediate part of their action via oxidative stress. Therefore, reducing oxidative stress appears to be a rational choice for the prevention and reduction in the rate of progression of these neurological disorders. This review provides a brief description of the epidemiology and pathogenesis of PD and AD, and the scientific rationale for the use of multiple antioxidants in the prevention of these neurological diseases.
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PMID:Can we prevent Parkinson's and Alzheimer's disease? 1459 87

Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in Parkinson's disease (PD) and other neurodegenerative disorders. We have investigated the effect of UPS inhibition on the metabolism of alpha-synuclein (SYN) and parkin, two proteins genetically and histopathologically associated to PD. Pharmacological inhibition of proteasome induced accumulation of both parkin and SYN in transfected PC12 cells. We found that this effect was caused by increased protein synthesis rather than impairment of protein degradation, suggesting that inhibition of the UPS might lead to non-specific up-regulation of cytomegalovirus (CMV)-driven transcription. To investigate whether endogenous parkin and SYN can be substrate of the UPS, untransfected PC12 cells and primary mesencephalic neurones were exposed to proteasome inhibitors, and parkin and SYN expression was evaluated at both protein and mRNA level. Under these conditions, we found that proteasome inhibitors did not affect the level of endogenous parkin and SYN. However, we confirmed that dopaminergic neurones were selectively vulnerable to the toxicity of proteasome inhibitors. Our results indicate that studies involving the use of proteasome inhibitors, particularly those in which proteins are expressed from a heterologous promoter, are subjected to potential artefacts that need to be considered for the interpretation of the role of UPS in PD pathogenesis.
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PMID:Proteasome inhibition and aggregation in Parkinson's disease: a comparative study in untransfected and transfected cells. 1472 Feb 4

Parkinson's disease patients frequently have symptoms and signs of autonomic nervous dysfunction that are the source of considerable disability. Recent studies have revealed that most patients with Parkinson's disease, and all with Parkinson's disease-associated orthostatic hypotension, have a loss of cardiac sympathetic innervation. Familial Parkinson's disease, caused by mutation of the gene encoding alpha-synuclein, also features orthostatic hypotension, sympathetic neurocirculatory failure and cardiac sympathetic denervation. We have recently described a whole-gene triplication of alpha-synuclein causing Lewy body parkinsonism in a large, well characterized family called the 'Iowa kindred'. Here we report the results of cardiac PET scanning using the sympathoneural imaging agent, 6-[18F]fluorodopamine in affected and unaffected members of this kindred. Four family members were studied, two with parkinsonism, one clinically normal and one with benign essential tremor alone. Both affected members had obvious loss of cardiac sympathetic innervation; the unaffected member had normal innervation, as did the member with isolated essential tremor. The results indicate that, in this family, where disease is caused by overexpression of normal alpha-synuclein, cardiac sympathetic denervation cosegregates with parkinsonism. Post-mortem studies have demonstrated synuclein-positive Lewy body formation in the brains of individuals with parkinsonism who were also in the family described here and who also carry this triplication. These results indicate that both parkinsonism and cardiac sympathetic denervation can result from an excess of normal synuclein.
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PMID:Association between cardiac denervation and parkinsonism caused by alpha-synuclein gene triplication. 1473 56


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