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

Once thought to be a single pathological disease state, amyotrophic lateral sclerosis (ALS) is now recognized to be the limited phenotypic expression of a complex, heterogeneous group of biological processes, resulting in an unrelenting loss of motor neurons. On average, individuals affected with the disease live <5 years. In this article, the complex nature of the pathogenesis of ALS, including features of age dependency, environmental associations, and genetics, is reviewed. Once held to be uncommon, it is now clear that ALS is associated with a frontotemporal dementia and that this process may reflect disturbances in the microtubule-associated tau protein metabolism. The motor neuron ultimately succumbs in a state where significant disruptions in neurofilament metabolism, mitochondrial function, and management of oxidative stress exist. The microenvironment of the neuron becomes a complex milieu in which high levels of glutamate provide a source of chronic excitatory neurotoxicity, and the contributions of activated microglial cells lead to further cascades of motor neuron death, perhaps serving to propagate the disease once established. The final process of motor neuron death encompasses many features of apoptosis, but it is clear that this alone cannot account for all features of motor neuron loss and that aspects of a necrosis-apoptosis continuum are at play. Designing pharmacological strategies to mitigate against this process thus becomes an increasingly complex issue, which is reviewed in this article.
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PMID:The basic aspects of therapeutics in amyotrophic lateral sclerosis. 1278 45

The Hohara village of the Kii peninsula is one of the high incidence ALS foci, and the high incidence was reported to have ended in early 1980s. However, we have found the ALS incidence rate has been still high, more than 100 times of the other areas of Japan. In addition, we have found many cases of parkinsonism-dementia complex (PDC). ALS and PDC often occur simultaneously in a single patient or in a single family. Family history was positive in more than 70% of patients. ALS and PDC showed common neuropathological findings consisting of ALS pathology and many neurofibrillary tangles (NFT) without senile plagues, and isoform pattern of NFT tau protein was similar to that of Alzheimer disease (AD), but different from that of progressive supranuclear palsy (PSP) or Pick's disease (PiD). Kii ALS/PDC may be a novel tauopathy that differ from AD, PSP or PiD.
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PMID:[Amyotrophic lateral sclerosis-parkinsonism-dementia complex of the Kii Peninsula of Japan]. 1278 69

Amyotrophic lateral sclerosis/parkinsonism-dementia complex of the Kii peninsula (Kii ALS/PDC) is a neurodegenerative disorder endemic to natives in the southern coast area of the Kii peninsula of Japan. The disorder closely resembles Guamanian ALS/PDC clinically and neuropathologically. The characteristic neuropathological finding is abundant neurofibrillary tangles (NFTs) without amyloid deposition. To elucidate the biochemical properties of hyperphosphorylated tau protein, the major component of the NFTs, we examined Kii ALS/PDC brains by immunoblotting and immunohistochemical analysis using well-characterized anti-tau antibodies specific to phosphorylation-dependent or -independent epitopes. Hyperphosphorylated tau in Kii ALS/PDC had phosphorylated epitopes common to tau of paired helical filaments (PHFs) in Alzheimer disease (AD): immunoblot showed triplet bands composed of 6 tau isoforms. Ultrastructurally, NFTs revealed a twisted filamentous shape similar to PHF of AD. The biochemical properties of its phosphorylated tau protein and the ultrastructural characteristics of the NFTs of Kii ALS/PDC are very similar, if not identical, to PHF tau in AD, although they are different taupopathies.
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PMID:Biochemical and ultrastructural study of neurofibrillary tangles in amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii peninsula of Japan. 1290 4

Neurofilaments are neuron-specific intermediate filaments. They are classed into three groups according to their molecular masses: neurofilament heavy, middle and light chains (NF-H, NF-M and NF-L). Neurofilaments assemble and form through the association of their central alpha-helical coiled-coil rod domains. NF-H and NF-M are distinct from NF-L as they contain a carboxyl-terminal tail domain, which appears to form connections with adjacent structures and other neurofilaments. Together with other axonal components such as microtubules, they form the dynamic axonal cytoskeleton. They maintain and regulate neuronal cytoskeletal plasticity through the regulation of neurite outgrowth, axonal caliber and axonal transport. Neurofilaments contain KSP repeats that are consensus motifs for the proline-directed kinases and are extensively phosphorylated in vivo, and their functions are thought to be regulated through their phosphorylation. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed kinase, whose activity is restricted to the neuron through the neuronal-specific distribution of its activators p35 and p39. Cdk5 is the only kinase that affects the electrophoretic mobility of human NF-H and is thought to be the major neurofilament kinase. Cdk5 is involved in crosstalk with other signal transduction pathways such as the mitogen-activated protein kinase and myelin-associated glycoprotein pathways to influence the phosphorylation of neurofilaments and other cytoskeletal proteins. Both the hyperactivation of Cdk5 activity and subsequent hyperphosphorylation of neurofilaments and the microtubule-associated protein tau have been implicated in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis. Here we review the functions of neurofilaments and the significance of Cdk5 phosphorylation of neurofilaments.
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PMID:Cyclin-dependent kinase 5 in neurofilament function and regulation. 1467 12

Familial forms of amyotrophic lateral sclerosis (ALS) can be caused by mutations in copper, zinc-superoxide dismutase (SOD1). Mice expressing SOD1 mutants demonstrate a robust neuroinflammatory reaction characterized, in part, by up-regulation of tumor necrosis factor alpha (TNFalpha) and its primary receptor TNF-RI. In an effort to identify small molecule inhibitors of neuroinflammation useful in treatment of ALS, a microglial culture system was established to identify TNFalpha antagonists. Walker EOC-20 microglia cells were stimulated with recombinant TNFalpha, with or without inhibitors, and the cell response was indexed by NO2- output. Three hundred and fifty-five rationally selected compounds were included in this bioassay. The arachidonic acid 5-lipoxygenase (5LOX) and tyrosine kinase inhibitor nordihydroguaiaretic acid (NDGA), a natural dicatechol, was one of the most potent non-cytotoxic antagonists tested (IC50 8 +/- 3 microm). Investigation of the G93A-SOD1 mouse model for ALS revealed increased message and protein levels of 5LOX at 120 days of age. Oral NDGA (2500 p.p.m.) significantly extended lifespan and slowed motor dysfunction in this mouse, when administration was begun relatively late in life (90 days). NDGA extended median total lifespan of G93A-SOD1 mice by 10%, and life expectancy following start of treatment was extended by 32%. Disease-associated gliosis and cleaved microtubule-associated tau protein, an indicator of axon damage, were likewise reduced by NDGA. Thus, TNFalpha antagonists and especially 5LOX inhibitors might offer new opportunities for treatment of ALS.
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PMID:The arachidonic acid 5-lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor alpha activation of microglia and extends survival of G93A-SOD1 transgenic mice. 1537 94

Abundant abnormal aggregates of cytoskeletal proteins are neuropathological signatures of many neurodegenerative diseases that are broadly classified by filamentous aggregates of neuronal intermediate filament (IF) proteins, or by inclusions containing the microtubule-associated protein (MAP) tau. The discovery of mutations in neuronal IF and tau genes firmly establishes the importance of neuronal IF proteins and tau in the pathogenesis of neurodegenerative diseases. Multiple IF gene mutations are pathogenic for Charcot-Marie-Tooth (CMT) disease and amyotrophic lateral sclerosis (ALS)--in addition to those in the copper/zinc superoxide dismutase-1 (SOD1) gene. Tau gene mutations are pathogenic for frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and tau polymorphisms are genetic risk factors for sporadic progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Thus, IF and tau abnormalities are linked directly to the aetiology and pathogenesis of neurodegenerative diseases. In vitro and transgenic animal models are being used to demonstrate that different mutations impair protein function, promote tau fibrilization, or perturb tau gene splicing, leading to aberrant and distinct tau aggregates. For recognition of these disorders at neuropathological examination, immunohistochemistry is needed, and this may be combined with biochemistry and molecular genetics to properly determine the nosology of a particular case. As reviewed here, the identification of molecular genetic defects and biochemical alterations in cytoskeletal proteins of human neurodegenerative diseases has facilitated experimental studies and will promote the development of assays of molecules which inhibit abnormal neuronal IF and tau protein inclusions.
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PMID:The cytoskeleton in neurodegenerative diseases. 1549 40

Biomarkers are very important indicators of normal and abnormal biological processes. Specific changes in pathologies, biochemistries and genetics can give us comprehensive information regarding the nature of any particular disease. A good biomarker should be precise and reliable, distinguishable between normal and interested disease, and differential between different diseases. It is believed that biomarkers have great potential in predicting chances for diseases, aiding in early diagnosis, and setting standards for the development of new remedies to treat diseases. New technologies have enabled scientists to identify biomarkers of several different neurodegenerative diseases. The followings, for instance, are only a few of the many new biomarkers that have been recently identified: the phosphorylated tau protein and aggregated Beta-amyloid peptide for Alzheimer's disease (AD), Alpha-synuclein contained Lewy bodies and altered dopamine transporter (DAT) imaging for Parkinson's disease (PD), SOD mutations for familial amyotrophic lateral sclerosis (ALS), and CAG repeats resulted from Huntington's gene mutations in Huntington's disease (HD). This article will focus on the most-recent findings of biomarkers belonging to the four mentioned neurodegenerative diseases.
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PMID:Biomarkers of neurodegenerative disorders: how good are they? 1553 67

An update of the endemic parkinsonism-dementia complex (PDC) frequently associated with amyotrophic lateral sclerosis (ALS) in the high prevalence ALS focus of the Kii peninsula of Japan is presented. The initial symptom was parkinsonian gait or hypobulia/amnesia, which was followed by akinesia, rigidity, occasional tremor, bradyphrenia, abulia and amnesia, and finally by akinetic mutism. In several years, most of the patients developed ALS symptoms such as muscle atrophy, bulbar palsy, and upper motor neuron signs. Magnetic resonance imaging and computed tomography of the brain showed marked atrophy of the temporal and frontal lobes and the cerebral blood flow reduction on single-photon emission computed tomography. Marked loss of nerve cells associated with abundant neurofibrillar tangles (NFTs) in the entire central nervous system, most predominantly in the brainstem and temporal lobe was characteristic. Concomitant ALS pathology involving the upper and lower motor neurons was common, and senile plaques were absent in most cases. NFTs consisted of twisted tubules on electron microscopy. Western blot of tau protein showed three bands consisting of six tau isoforms, similar to those of Alzheimer's disease. A family history of ALS/PDC was recorded in more than 70% of patients, but no abnormal mutation or polymorphism was found in the genes of SOD1, tau, and apolipoprotein E. Familial nature and continuing morbidity of Kii ALS/PDC suggest that genetic factors may be more likely in its pathogenesis.
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PMID:Atypical parkinsonism of Japan: amyotrophic lateral sclerosis-parkinsonism-dementia complex of the Kii peninsula of Japan (Muro disease): an update. 1609 99

Aluminum is environmentally abundant, but not an essential element. Aluminum has been associated with several neurodegenerative diseases, such as dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii peninsula and Guam, and in particular, Alzheimer's disease. Although this association remains controversial, there is increasing evidence which suggests the implication of metal homeostasis in the pathogenesis of Alzheimer's disease. Aluminum, zinc, copper, and iron cause the conformational changes of Alzheimer's amyloid-beta protein. Al causes the accumulation of tau protein and amyloid-beta protein in experimental animals. Aluminum induces neuronal apoptosis in vivo as well as in vitro. Furthermore, a relationship between aluminum and the iron-homeostasis or calcium-homeostasis has been suggested. Based on these findings, the characteristics of aluminum neurotoxicity are reviewed, and the potential link between aluminum and neurodegenerative diseases is reconsidered.
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PMID:Effects of aluminum on the nervous system and its possible link with neurodegenerative diseases. 1630 86

The authors have characterized frontal cortical tau protein in cognitively intact (4) and cognitively impaired (ALSci, 4) ALS patients and compared it with control (2) or Alzheimer disease (AD, 1)- derived tau. The authors observed expression of both 3R and 4R tau isoforms; increased insoluble tau protein; phosphatase resistance; and hyperphosphorylation at T175, S208, and S210. Soluble tau from both AD and ALSci was also phosphorylated at S237. Tau hyperphosphorylation is associated with ALS.
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PMID:Tau protein hyperphosphorylation in sporadic ALS with cognitive impairment. 1676 62


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