Showing papers by "Michel Goedert published in 1997"

Alpha-synuclein in Lewy bodies.

Abstract: Lewy bodies, a defining pathological characteristic of Parkinson's disease and dementia with Lewy bodies (DLB)1,2,3,4, constitute the second most common nerve cell pathology, after the neurofibrillary lesions of Alzheimer's disease. Their formation may cause neurodegeneration, but their biochemical composition is unknown. Neurofilaments and ubiquitin are present5,6,7,8, but it is unclear whether they are major components of the filamentous material of the Lewy body9,10. Here we describe strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease11. α-Synuclein may be the main component of the Lewy body in Parkinson's disease. We also show staining for α-synuclein of Lewy bodies from DLB, indicating that the Lewy bodies from these two diseases may have identical compositions.

Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases

Abstract: A cDNA was cloned that encodes human stress-activated protein kinase-4 (SAPK4), a novel MAP kinase family member whose amino acid sequence is approximately 60% identical to that of the other three SAP kinases which contain a TGY motif in their activation domain. The mRNA encoding SAPK4 was found to be widely distributed in human tissues. When expressed in KB cells, SAPK4 was activated in response to cellular stresses and pro-inflammatory cytokines, in a manner similar to other SAPKs. SAPK4 was activated in vitro by SKK3 (also called MKK6) or when co-transfected with SKK3 into COS cells. SKK3 was the only activator of SAPK4 that was induced when KB cells were exposed to a cellular stress or stimulated with interleukin-1. These findings indicate that SKK3 mediates the activation of SAPK4. The substrate specificity of SAPK4 in vitro was similar to that of SAPK3. Both enzymes phosphorylated the transcription factors ATF2, Elk-1 and SAP-1 at similar rates, but were far less effective than SAPK2a (also called RK/p38) or SAPK2b (also called p38beta) in activating MAPKAP kinase-2 and MAPKAP kinase-3. Unlike SAPK1 (also called JNK), SAPK3 and SAPK4 did not phosphorylate the activation domain of c-Jun. Unlike SAPK2a and SAPK2b, SAPK4 and SAPK3 were not inhibited by the drugs SB 203580 and SB 202190. Our results suggest that cellular functions previously attributed to SAPK1 and/or SAPK2 may be mediated by SAPK3 or SAPK4.

Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6): Comparison of the specificities of SAPK3 and SAPK2 (RK/p38)

Abstract: Stress-activated protein kinase-3 (SAPK3), a recently described MAP kinase family member with a wide-spread tissue distribution, was transfected into several mammalian cell lines and shown to be activated in response to cellular stresses, interleukin-1 (IL-1) and tumour necrosis factor (TNF) in a similar manner to SAPK1 (also termed JNK) and SAPK2 (also termed p38, RK, CSBP and Mxi2). SAPK3 and SAPK2 were activated at similar rates in vitro by SAPKK3 (also termed MKK6), and SAPKK3 was the only activator of SAPK3 that was induced when KB or 293 cells were exposed to cellular stresses or stimulated with IL-1 or TNF. Co-transfection with SAPKK3 induced SAPK3 activity and greatly enhanced activation in response to osmotic shock. These experiments indicate that SAPKK3 mediates the activation of SAPK3 in several mammalian cells. SAPK3 and SAPK2 phosphorylated a number of proteins at similar rates, including the transcription factors ATF2, Elk-1 and SAP1, but SAPK3 was far less effective than SAPK2 in activating MAPKAP kinase-2 and MAPKAP kinase-3. Unlike SAPK2, SAPK3 was not inhibited by the drug SB 203580. SAPK3 phosphorylated ATF2 at Thr69, Thr71 and Ser90, the same residues phosphorylated by SAPK1, whereas SAPK2 only phosphorylated Thr69 and Thr71. Our results suggest that cellular functions previously attributed to SAPK1 and/or SAPK2 may be mediated by SAPK3.

Familial multiple system tauopathy with presenile dementia: A disease with abundant neuronal and glial tau filaments

Abstract: Neurofibrillary lesions made of hyperphosphorylated microtubule-associated protein tau constitute not only one of the defining neuropathological features of Alzheimer disease but also are present in a number of other neurodegenerative diseases with dementia. Here we describe a novel autosomal dominant disease named familial “multiple system tauopathy with presenile dementia,” which is characterized by abundant fibrillary deposits of tau protein in both neurons and glial cells. There are no detectable deposits of β-amyloid. The tau deposits are in the form of twisted filaments that differ in diameter and periodicity from the paired helical filaments of Alzheimer disease. They are stained by both phosphorylation-independent and -dependent anti-tau antibodies. Moreover, tau immunoreactivity coexists with heparan sulfate in affected nerve and glial cells. Tau protein extracted from filaments of familial multiple system tauopathy with presenile dementia shows a minor 72-kDa band and two major bands of 64 and 68 kDa that contain mainly hyperphosphorylated four-repeat tau isoforms of 383 and 412 amino acids.

Argyrophilic grain disease: widespread hyperphosphorylation of tau protein in limbic neurons

Abstract: Argyrophilic grains (ArG) and coiled bodies of argyrophilic grain disease (AgD) and the neurofibrillary lesions of Alzheimer’s disease (AD) share similar antigenic determinants, among them hyperphosphorylated microtubule-associated protein tau. Nothing is known about the mechanisms underlying tau hyperphosphorylation in AgD, the hyperphosphorylated sites or the intracellular distribution of abnormally phosphorylated tau. We have analysed brain tissue sections from 41 subjects with AgD with a panel of phosphorylation-dependent (AT270, AT8, Tau-1, AT180, 12E8, PHF-1 and AT100) and phosphorylation-independent anti-tau antibodies (N-tau 5, 304, 189 and 134). All antibodies labelled ArG, coiled bodies and neurofibrillary lesions, with the exception of antibody 12E8, which stained a subset of neurofibrillary tangles, but no ArG or coiled bodies. Most pyramidal neurons in areas rich in ArG showed diffuse granular tau labelling in cell bodies and dendrites. Only very few tau-positive cells also contained neurofibrillary tangles. Phosphorylation-dependent anti-tau antibodies also stained a felt-like network of Gallyas-negative filiform neurites in layer CA1 of the hippocampus and in layer pre-Β of the transentorhinal cortex. These results demonstrate a widespread hyperphosphorylation of tau protein in the somatodendritic domain of neurons in AgD, in addition to silver grains in the neuropil. Unlike in AD, tau hyperphosphorylation in the somatodendritic domain in AgD does not appear to be followed by neurofibrillary tangle formation, even in the presence of widespread ArG in the neuropil. Furthermore, our data suggest that no strict correlation exists between the presence or density of ArG in the limbic area and the occurrence of dementia.

The Neurofibrillary Pathology of Alzheimer's Disease:

Abstract: Abundant neurofibrillary lesions in certain brain regions constitute one of the defining neuropathological characteristics of Alzheimer's disease, where their presence correlates with the degree of dementia. An understanding of the mechanisms that lead to the neurofibrillary pathology is critical for elucidating the pathogenesis of Alzheimer's disease and for developing effective therapeutic strategies. Neurofibrillary lesions consist of neurofibrillary tangles, neuropil threads, and abnormal neurites. Ultrastructurally, each of these lesions consists of abnormal paired helical and straight filaments. These filaments are made of the six brain isoforms of microtubule-associated protein tau in a hyperphosphorylated and an abnormally phosphorylated state. Several candidate protein kinases and protein phosphatases for the hyperphos phorylation of tau have been identified. Moreover, recent results suggest that an interaction between tau protein and sulfated glycosaminoglycans may play an important role in indu...

Familial multiple-system tauopathy with presenile dementia is localized to chromosome 17.

Abstract: Summary An autosomal dominant presenile dementia affecting 39 individuals in a seven-generation, 383-member pedigree has been studied at Indiana University. In the affected members of this family, clinical symptoms occurred early in life, with an average age at onset of 48.8 years. The presenting clinical features include disequilibrium, neck stiffness, dysphagia, and memory loss. As the disease progresses, further cognitive decline, superior-gaze palsy, and dystaxia also are observed. The average duration from onset of symptoms to death is ∼10 years. Neuropathologic studies of nine affected individuals showed neuronal loss in several areas of the CNS, as well as argentophilic tau-immunopositive inclusions in neurons and in oligodendroglia. A limited genomic screen by use of DNA samples from 28 family members localized the gene for this disorder to a 3-cM region on chromosome 17, between the markers THRA1 and D17S791. The gene for tau also was analyzed, through samples from the family.

MAP kinases: polypeptides, polynucleotides and uses thereof

Abstract: A substantially pure stress-activated protein kinase comprising the amino acid sequence (I) or a variant, fragment, fusion or derivative thereof, or a fusion of a said variant or fragment or derivative. The above stress-activated protein kinase and the related stress-activated protein kinase SAPK3 are useful in screening assays for drugs.