Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin-immunoreactive dystrophic neurites in the CA2/3 region of the hippocampus are characteristic of diffuse Lewy body disease (DLBD). The origin of dystrophic CA2/3 neurites is unknown, but their extent correlates with the number of cortical Lewy bodies (LBs). To examine the molecular composition of these lesions, hippocampal sections were obtained at postmortem from cases of DLBD, Parkinson's disease and Alzheimer's disease. The tissue samples were fixed in a variety of fixatives and immunostained with antibodies to ubiquitin, ubiquitin C-terminal hydrolase (PGP9.5), neurofilament protein subunits, tau protein, paired helical filaments and tyrosine hydroxylase (TH). In addition to being ubiquitin positive, both cortical LBs and CA2/3 dystrophic neurites were positive with a neurofilament monoclonal antibody (RM032) and PGP9.5; however, fewer lesions were detected with these antibodies compared to ubiquitin immunocytochemistry. The dystrophic CA2/3 neurites were not stained with antibodies to tau proteins, paired helical filaments or TH. Absence of TH immunoreactivity suggests that CA2/3 neuritic processes are not derived from brain stem dopaminergic afferents to the hippocampus. Since CA2/3 neurites are immunologically similar to cortical LB, the pathogenesis of these lesions may be similar. Characterization of dystrophic CA2/3 neurites and cortical LBs may clarify how these lesions contribute to the emergence of dementia in DLBD.
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PMID:Immunoreactivity profile of hippocampal CA2/3 neurites in diffuse Lewy body disease. 791 27

This report concerns an immunocytochemical and ultrastructural study of the motor cortices of 11 patients with amyotrophic lateral sclerosis (ALS). Specimens from 12 normal individuals served as controls. Antibodies against phosphorylated neurofilament (PNF; 200 kDa), ubiquitin, glial fibrillary acidic protein (GFAP) and phosphorylated tau protein were used. The pyramidal cells of layer III of all ALS patients were stained, with varying intensities, by the antibody to PNF. By contrast, Betz cells reacted less frequently with this antibody. Staining for GFAP was noted in numerous astrocytes in layer III and at the transition between white matter and motor cortex of most patients. Ubiquitin-positive inclusions were only occasionally seen in Betz cell and pyramidal cell of layer V. These observations indicate that alterations of the motor cortex occur first in the pyramidal cells of layer III rather than in Betz cells. Pyramidal cells and Betz cells were not stained by the antibody to phosphorylated tau protein. In controls, pyramidal cells and Betz cells were less frequently stained with the anti-neurofilament antibody than those from ALS patients. Immunoreactivity of GFAP in layer III and at the junction of white matter and motor cortex was observed in only one patient. Ultrastructural examination revealed that the Betz cells of some ALS patients had Bunina bodies (BB), Lewy body-like inclusions (LBI) and skein-like inclusions (SI), as well as bundles of filaments that were thicker than neurofilaments; some of these filaments appeared to be constricted. The incidence of these inclusions was lower than that seen in anterior horn neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Immunocytochemical and ultrastructural studies of the motor cortex in amyotrophic lateral sclerosis. 809 50

Characteristic changes appearing in the biopsied olfactory mucosa of Alzheimer's disease (AD) patients were investigated using immunohistochemical staining. Specimens were obtained from 6 patients who were clinically diagnosed with AD, 2 patients with cerebrovascular dementia and 5 age-matched patients with olfactory disturbance without dementia. In most AD cases, polyclonal tau protein immunoreactivity was seen in the dendrites, perikarya of the olfactory receptor cells in the olfactory epithelium and the olfactory nerve bundles in the lamina propria. In a few cases, tau protein immunoreactivity was found in the extracellular mass in the epithelium. Ubiquitin immunoreactivity was seen is the dendrites of olfactory receptor cells. On the other hand, in control cases, only dendrites and olfactory nerve bundles reacted to anti-polyclonal tau protein antiserum in a few cases. These results indicate that the neurofibrillary tangle-like tau protein immunoreactivity in the perikarya senile plaque-like extracellular mass and ubiquitin immunoreactivity in the olfactory epithelium were characteristic changes in AD, and olfactory mucosal biopsy is a useful method for the definitive diagnosis of AD.
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PMID:[Definitive diagnosis of Alzheimer's disease using olfactory mucosal biopsy]. 817 37

Characteristic changes that appear in the biopsied olfactory mucosa of patients with Alzheimer's disease (AD) were examined with immunohistochemical staining. Specimens were obtained from patients with clinical diagnoses of AD. Patients with vascular dementia and age-matched patients without dementia were used for controls. In most AD cases, neurofibrillary tangle-like abnormal tau protein (Tau) immunoreactivity was seen in the dendrites and perikarya of the olfactory receptor cells and in the nerve bundles. A senile plaque-like extracellular mass was found in the olfactory epithelium, and it reacted strongly to an anti-Tau antiserum and weakly to an anti-amyloid-beta protein antiserum. Ubiquitin (Ubq) immunoreactivity was also observed in the dendrites. Tau immunoreactivity of the perikarya and extracellular mass, and Ubq immunoreactivity were especially characteristic of the olfactory mucosa of AD patients. From these results, it is clear that the same pathologic changes in the brain are also present in the olfactory mucosa of patients with AD. Not only disruption of the central olfactory pathway, but also an olfactory disturbance of AD patients is caused by peripheral changes. Furthermore, an olfactory mucosal biopsy could be a useful method for a definitive diagnosis of AD.
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PMID:Pathology of olfactory mucosa in patients with Alzheimer's disease. 820 7

The effects of permanent focal cerebral ischaemia on Alz-50 and ubiquitin antibody immunohistochemical staining were investigated in vivo in the cat. Alz-50 and ubiquitin antibody staining was compared to the distribution of ischaemic cell damage. Six hours following permanent occlusion of one middle cerebral artery, Alz-50 immunoreactivity was present in neurones in the ipsilateral ischaemic cerebral cortex and caudate nucleus but not in any region of the contralateral hemisphere or in sham-operated cats. Only a proportion of neurones were stained with Alz-50 and these did not have the shrunken, pyknotic appearance characteristic of irreversible ischaemic cell damage. Ubiquitin immunoreactivity was also increased in the ischaemic hemisphere, again only a proportion of neurones were stained. The Alz-50 antibody recognises the microtubule-associated protein tau and stains neurofibrillary tangles as well as neurones vulnerable to neurofibrillary change in tissue sections of Alzheimer brain. The results indicate that there are changes in tau protein in response to an ischaemic insult, but only in some neurones, which may reflect an early stage of the degenerative process. Increased ubiquitin immunoreactivity may be a response to the presence of abnormal proteins, including tau, which are induced by an ischaemic challenge.
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PMID:Alz-50 and ubiquitin immunoreactivity is induced by permanent focal cerebral ischaemia in the cat. 831 Aug 18

In this study of an aged wolverine (Gulo gulo), we document neuropathologic lesions (cerebral amyloid angiopathy (CAA), neuritic plaques (NPs), neurofibrillary tangles (NFTs), and granulovacuolar degeneration strikingly similar to those present in aging and Alzheimer's disease (AD), with the additional finding of concurrent cerebral hemorrhage. A beta immunoreactive cerebral amyloid angiopathy and senile plaques (neuritic and diffuse) were present throughout the cerebral cortex and hippocampus. Ubiquitin immunoreactivity was noted in peripheral portions of some of the plaques. Argyrophilic intracellular neurofibrillary tangles containing abnormally phosphorylated (Ser 202) tau protein were present within cortical and hippocampal neurons. The wolverine should be added to the list of nonhuman species (dogs, nonhuman primates, polar bears) with amyloid deposits similar to those in aged humans and in humans with AD. The aged wolverine appears to be distinct from other nonhuman species in possessing plaques and NFTs, as well as other histologic cerebral lesions frequently associated with AD.
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PMID:A beta-associated cerebral angiopathy and senile plaques with neurofibrillary tangles and cerebral hemorrhage in an aged wolverine (Gulo gulo). 874 5

Multiple factors have been hypothesized over the last century to be causative or contributory for Parkinson's disease. Hereditary factors have recently emerged as a major focus of Parkinson's disease research. Until recently most of the research on the etiology of Parkinson's disease concentrated on environmental factors, and the possibility that genetic factors contribute significantly to the pathogenesis of Parkinson's disease has been neglected. However, it has become increasingly apparent that even in sporadic cases, the disease most likely reflects a combination of genetic susceptibility and an unknown environmental insult. Moreover, the identification of genes and proteins that may cause hereditary parkinsonism substantially contributes to our ability to understand the pathogenesis of Parkinson's disease and may help in the early identification of the disease and its treatment. The discovery of alpha-synuclein mutations in families with autosomal dominant Parkinson's disease sheds light on its role in sporadic Parkinson's disease. It seems that this protein tends to aggregate when the cellular milieu is altered [14-16]. The question as to the exact changes that cause its deposition remains open. One of the major possibilities is oxidative stress [16]. The role of these aggregates in neuronal cell death is also still unclear. Transgenic mice expressing wild-type human alpha-synuclein developed progressive accumulation of alpha-synuclein and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus and the substantia nigra. These alterations were associated with loss of dopaminergic terminals and motor impairments [24]. This finding suggests that accumulation of alpha-synuclein may play a causal role in sporadic Parkinson's disease as well. The parkin protein seems to be a crucial survival factor for nigral neurons [15]. The parkin protein is related to the ubiquitin pathway, which is important in the elimination of damaged proteins. Ubiquitin-mediated degradation of proteins plays a central role in the control of numerous processes, including signal transduction, receptor and transcriptional regulations, programmed cell death, and breakdown of abnormal proteins that may interfere with normal cell functions. Further studies on the function of Parkin protein and its relation to the ubiquitin pathway could elucidate at least one of the molecular mechanisms of nigral neuronal death. A mutation in the ubiquitin carboxy-teminal hydrolase L1 gene also implies the importance of the ubiquitin pathway in Parkinson's disease. Abnormal tau protein was found to be the cause of familial frontotemporal dementia and parkinsonism. It tends to form filamentous structures, which may lead to neuronal death. Elucidation of the molecular mechanism of neuronal death in this disease may contribute to our understanding of sporadic diseases with tau accumulation, such as corticobasal degeneration, progressive supranuclear palsy, Pick's disease, Alzheimer's disease and possibly also the pathogenesis of Parkinson's disease. Other genetic loci have been identified by linkage analysis of patients with familial parkinsonism. These loci conceal other genes and proteins that may be pivotal factors in the pathogenesis of Parkinson's disease. The discovery of genetic mutations in patients with parkinsonism may offer us new insights into the understanding of the pathways leading to neuronal death and development of Parkinson's disease. It may also help in the early identification of susceptible people to this disease and possibly in developing new treatment strategies.
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PMID:Heredity in Parkinson's disease: new findings. 1143 38

Ubiquitin-positive dots and granular structures from insular, temporopolar, hippocampal and parahippocampal cortices of nondemented and Alzheimer's disease patients have been studied with both light and electron microscopes. The relationship of both types of ubiquitin-positive elements with pretangle neurons and neurofibrillary tangles has been analyzed by comparing adjacent or nearly adjacent sections immunostained for either ubiquitin or an antibody that recognizes hyperphosphorylated tau protein (AT-8). Moreover, a double protocol with both antibodies was used in order to obtain double-stained sections. The presence of ubiquitin-positive dots and granular structures precedes the appearance of pretangle neurons in the youngest cases. In aged and Alzheimer disease cases, both types of ubiquitin-positive elements decrease in number as pretangle neurons are replaced by mature and ghost tangles. Ultrastructurally, dots and granular structures appear to be degenerating neuronal processes and/or terminals. Our results suggest that the degeneration of these processes and/or terminals might be related with the initiation of neurofibrillary degeneration.
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PMID:Ubiquitinated granular structures and initial neurofibrillary changes in the human brain. 1170 Nov 49

We report a familial disorder occurring in three patients that presented as frontotemporal dementia (FTD). A neuropathological study was performed in a 58-year-old patient, who developed FTD 2 years prior to the onset of motor neuron disease (MND), and died at age 62. Lesions indicative of associated MND were observed: neuronal loss in the anterior horns of the spinal cord, Bunina bodies, axonal spheroids, degeneration of the pyramidal tracts, and of FTD: decreased neuronal density and laminar microvacuolation of layers II and III in the frontal and temporal cortex. Ubiquitin-only-immunoreactive changes were found in the spinal cord and medulla, but were absent from the temporal and frontal cortex. There were also widespread deposits of various neuronal and glial inclusions containing abnormally phosphorylated tau protein, the Western blotting pattern of which was characterized by two major bands of 64 and 69 kDa. There were no abnormalities of the entire coding sequences of microtubule-associated protein tau (MAPT) and copper-zinc superoxide dismutase (SOD(1)) genes. Our results suggest that FTD associated with MND can be caused by a larger spectrum of neuropathological lesions than commonly accepted.
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PMID:Frontotemporal dementia, motor neuron disease and tauopathy: clinical and neuropathological study in a family. 1596 97

Genetic studies have led to major discoveries in the pathogenesis of various neurodegenerative diseases. Ubiquitin-positive familial frontotemporal dementia was recently found to be caused by mutations in the progranulin gene (PGRN), and the major constituent of the inclusions, TDP-43, was subsequently identified. The tau gene (MAPT) causes frontotemporal dementia with parkinsonism linked to chromosome 17. In Parkinson disease, LRRK2 mutations have emerged as a major cause of both familial and sporadic forms, adding to the previously known genes SNCA,PRKN,DJ1 and PINK1. Several genes have been implicated in Alzheimer disease, including the APP gene and the PSEN genes. Recently, variants in the sortilin-related receptor 1 gene, SORL1, were associated with Alzheimer disease.
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PMID:Etiology and pathophysiology of frontotemporal dementia, Parkinson disease and Alzheimer disease: lessons from genetic studies. 1832 68


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