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Understanding neurodegeneration : a neuropathologist’s perspective
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Revesz, Tamas (2020) Understanding neurodegeneration : a neuropathologist’s perspective. DSc thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3857599
Abstract
A.1.1 Our initial studies, published in Brain and Acta Neuropathologica aimed to extend our knowledge about the British pedigree and to understand the neuropathology of this condition (Ref: 1 current citations: 119; Ref: 2 current citations: 52; Ref: 3 current citations: 73).
A.1.2 In 1999 and 2000 our joint research led to the discovery of the causes of the two diseases, which we re-named familial British dementia (FBD) and familial Danish dementia (FDD). In these studies, we showed that both FBD and FDD are associated with unique mutations in the novel BRI2 gene. Our paper which dealt with the British condition was published in Nature (Ref: 4 current citations: 322) while the study about the Danish pedigree was published in the Proceedings of the National Academy of Science, USA (Ref: 5 current citations: 224). In these two seminal studies, we showed that by abolishing the normal stop codon, both mutations (a Stop-to-Arg point mutation in the British pedigree, and a 10-nucleotide insertion mutation in the Danish kindred) result in elongation of the BRI precursor protein. Furin-like processing of the mutated precursor proteins releases the novel, 34 amino acid-long amyloid peptides, ABri in FBD and ADan in FDD, which are different from one another in their 12 C-terminal amino acids.
A.1.3 The discovery of the causes of the two diseases triggered several further, biochemical and neuropathological studies (Refs: 6-14). Among others, we were the first, who were able to study with our newly generated antibodies specific to either ABri or ADan, the cerebral distribution of the ABri and ADan deposits in FBD and FDD cases, respectively. Among the many novel findings, our studies demonstrated that, as in Alzheimer’ disease, in both FBD and FDD there are amyloid plaques, cerebral amyloid angiopathy and neurofibrillary tangles, despite the fact that there is no similarity between the Alzheimer disease’s amyloid- peptide and the two closely related amyloid peptides, ABri and ADan, indicating a general link between cerebral amyloid formation and neurofibrillary degeneration. We also showed that, as in Alzheimer’s disease, the neurofibrillary tangles are composed of both major classes of the tau isoforms and that ultrastructurally the tau filaments forming neurofibrillary tangles are classical paired helical filaments in both FBD and FDD (Ref: 6 current citations: 94; Ref: 7 current citations: 86).
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Item Type: | Thesis (DSc) | ||||
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Subjects: | R Medicine > RC Internal medicine | ||||
Library of Congress Subject Headings (LCSH): | Nervous system -- Degeneration, Dementia, Movement disorders | ||||
Official Date: | 18 January 2020 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | DSc | ||||
Publication Status: | Unpublished | ||||
Format of File: | 19 pages | ||||
Language: | eng |
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