Gerstmann-Sträussler-Scheinker disease revisited: accumulation of covalently-linked multimers of internal prion protein fragments
| Autor: | Satish K. Nemani, Silvio Notari, Laura Cracco, Jody Lavrich, Ignazio Cali, Pierluigi Gambetti, Xiangzhu Xiao, Bernardino Ghetti, Witold K. Surewicz |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Epitope mapping Multimers lcsh:RC346-429 Pathology and Forensic Medicine 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Prion protein lcsh:Neurology. Diseases of the nervous system chemistry.chemical_classification Gerstmann-Straussler-Scheinker Disease Mass spectrometry Genetic heterogeneity Chemistry Research Conclusive evidence Creutzfeldt-Jakob disease nervous system diseases Amino acid Aggregate formation 030104 developmental biology Biochemistry Covalent bond Neurology (clinical) Variable number 030217 neurology & neurosurgery |
| Zdroj: | Acta Neuropathologica Communications, Vol 7, Iss 1, Pp 1-9 (2019) Acta Neuropathologica Communications |
| ISSN: | 2051-5960 |
| Popis: | Despite their phenotypic heterogeneity, most human prion diseases belong to two broadly defined groups: Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker disease (GSS). While the structural characteristics of the disease-related proteinase K-resistant prion protein (resPrPD) associated with the CJD group are fairly well established, many features of GSS-associated resPrPD are unclear. Electrophoretic profiles of resPrPD associated with GSS variants typically show 6–8 kDa bands corresponding to the internal PrP fragments as well as a variable number of higher molecular weight bands, the molecular nature of which has not been investigated. Here we have performed systematic studies of purified resPrPD species extracted from GSS cases with the A117V (GSSA117V) and F198S (GSSF198S) PrP gene mutations. The combined analysis based on epitope mapping, deglycosylation treatment and direct amino acid sequencing by mass spectrometry provided a conclusive evidence that high molecular weight resPrPD species seen in electrophoretic profiles represent covalently-linked multimers of the internal ~ 7 and ~ 8 kDa fragments. This finding reveals a mechanism of resPrPD aggregate formation that has not been previously established in prion diseases. Electronic supplementary material The online version of this article (10.1186/s40478-019-0734-2) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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