Showing papers by "Michel Goedert published in 1998"

α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies

Abstract: Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson’s disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson’s disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of α-synuclein, showing the presence of full-length or close to full-length α-synuclein. The number of α-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for α-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer’s disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-α-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended α-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that α-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.

Mutation in the tau gene in familial multiple system tauopathy with presenile dementia

Abstract: Familial multiple system tauopathy with presenile dementia (MSTD) is a neurodegenerative disease with an abundant filamentous tau protein pathology. It belongs to the group of familial frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17), a major class of inherited dementing disorders whose genetic basis is unknown. We now report a G to A transition in the intron following exon 10 of the gene for microtubule-associated protein tau in familial MSTD. The mutation is located at the 3′ neighboring nucleotide of the GT splice-donor site and disrupts a predicted stem-loop structure. We also report an abnormal preponderance of soluble tau protein isoforms with four microtubule-binding repeats over isoforms with three repeats in familial MSTD. This most likely accounts for our previous finding that sarkosyl-insoluble tau protein extracted from the filamentous deposits in familial MSTD consists only of tau isoforms with four repeats. These findings reveal that a departure from the normal ratio of four-repeat to three-repeat tau isoforms leads to the formation of abnormal tau filaments. The results show that dysregulation of tau protein production can cause neurodegeneration and imply that the FTDP-17 gene is the tau gene. This work has major implications for Alzheimer’s disease and other tauopathies.

Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia.

Abstract: The abnormal aggregation of proteins into fibrillar lesions is a neuropathological hallmark of several sporadic and hereditary neurodegenerative diseases For example, Lewy bodies (LBs) are intracytoplasmic filamentous inclusions that accumulate primarily in subcortical neurons of patients with Parkinson's disease (PD), or predominantly in neocortical neurons in a subtype of Alzheimer's disease (AD) known as the LB variant of AD (LBVAD) and in dementia with LBs (DLB) Aggregated neurofilament subunits and α-synuclein are major protein components of LBs, and these inclusions may contribute mechanistically to the degeneration of neurons in PD, DLB and LBVAD Here we review recent studies of the protein building blocks of LBs, as well as the role LBs play in the onset and progression of PD, DLB and LBVAD Increased understanding of the protein composition and pathological significance of LBs may provide insight into mechanisms of neuron dysfunction and death in other neurodegenerative disorders characterized by brain lesions containing massive deposits of proteinacious fibrils

Lewy body diseases and multiple system atrophy as alpha-synucleinopathies.

Abstract: Parkinson’s disease and dementia with Lewy bodies are among the most common neurodegenerative diseases. They share the Lewy body and the Lewy neurite as their defining neuropathological characteristics. Originally described in 1912 as a light-microscopic entity, the Lewy body was shown to be made of abnormal filaments in the 1960s. Over the past year, the biochemical nature of the Lewy body filament has been revealed. A large number of different proteins has been reported to be present in Lewy bodies and Lewy neurites by immunohistochemical methods. However, these findings do not permit us to distinguish between intrinsic Lewy body components and normal cellular constituents that get merely trapped in the filaments that make up the Lewy body. A similar problem plagued the field of the neurofibrillary lesions of Alzheimer’s disease over part of the 1980s. It was solved with the purification and analysis of paired helical and straight filaments, the filamentous constituents of the neurofibrillary lesions. Unfortunately, a similar approach with Lewy bodies has only met with partial success, mainly because Lewy bodies and Lewy neurites are much less abundant than neurofibrillary lesions. This was the situation until the middle of last year, when genetics came to the rescue, taking us straight to the very core of the Lewy body filament. In June 1997, Polymeropoulos et al reported a missense mutation in a-synuclein in a large pedigree with early-onset Parkinson’s disease and in three smaller, apparently unrelated kindreds. The mutation is an alanine to threonine change at residue 53 of a-synuclein, an abundant 140-amino acid presynaptic protein of unknown function. Somewhat surprisingly, rodent and zebrafinch asynucleins carry a threonine residue at position 53, like the mutated human protein. This, together with the fact that all families with the A53T mutation are of either Southern Italian or Greek origin, and that this part of Italy was colonized by Greece a long time ago, led some to propose that the A53T change may be nothing more than a rare benign polymorphism. However, the discovery earlier this year of an alanine to proline mutation at residue 30 of a-synuclein in a family of German descent with Parkinson’s disease, has settled this controversy in favour of the relevance of a-synuclein for the aetiology and pathogenesis of some familial cases of Parkinson’s disease. The two mutations in a-

Neurofibrillary pathology of Alzheimer's disease and other tauopathies.

Abstract: Publisher Summary Alzheimer's disease is the most common neurodegenerative disorder. It affects 15-20 million people worldwide and constitutes the fourth leading cause of death in the industrialized world. Its major symptoms are a progressive loss of memory and other cognitive functions, resulting in a severe and irreversible dementia. The intellectual decline is accompanied by the accumulation in the brain of insoluble fibrous material, extracellularly in the form of plaques composed of amyloid protein AP, and intracellularly in the form of neurofibrillary lesions. A study of the mechanisms that lead to the formation of plaques and neurofibrillary lesions is essential for an understanding of the pathogenesis of all forms of Alzheimer's disease. The extent and topographical distribution of neurofibrillary lesions provide a reliable pathological correlate of the degree of dementia. The formation of neurofibrillary lesions is therefore believed to lead to the symptoms of Alzheimer's disease, which result most probably from the degeneration of nerve cells in cerebral cortex and hippocampal formation, with ensuing neuronal cell loss and reduction in synapse number. The finding of large numbers of amyloid deposits in some cognitively normal individuals (also known as “pathological ageing”) has shown that amyloid deposits are not sufficient for dementia. In contrast, large numbers of neurofibrillary lesions in hippocampus and/or cerebral cortex are always accompanied by dementia. Over recent years, it has become apparent that in other forms of dementia filamentous tau deposits are frequently observed in the absence of amyloid deposits. This chapter reviews the tau pathology of Alzheimer's disease and other “tauopathies.”

Tau protein pathology in neurodegenerative

Abstract: LZHEIMER’S DISEASE (AD) and related dementiasare characterized by a progressive loss of memory,resulting in dementia and death. They affect over 20 million people worldwide and their incidence is expected to double over the next 30 years. There istherefore an urgent need to understand the mecha-nisms underlying the degeneration of nerve cells.While the patient is alive, the distinction between dif-ferent forms of dementia rests with clinical assess-ment. The diagnosis of a specific form of dementia isconfirmed at autopsy. Thus, a diagnosis of AD is madewhen a patient exhibits clinical evidence of progres-sive dementia and when a