Dementia with Lewy bodies—associated ß-synuclein mutations V70M and P123H cause mutation-specific neuropathological lesions
| Autor: | Sameehan Mahajani, Kristian Leite, Maryna Psol, Sebastian Kügler, Sofia Guerin Darvas, Mathias Bähr |
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| Rok vydání: | 2021 |
| Předmět: |
Lewy Body Disease
Male animal diseases Central nervous system Mutation Missense Biology medicine.disease_cause Cell Line 03 medical and health sciences beta-Synuclein 0302 clinical medicine Genetics medicine Animals Humans heterocyclic compounds Rats Wistar Molecular Biology Genetics (clinical) Aged 030304 developmental biology Neurons 0303 health sciences Mutation Dementia with Lewy bodies Neurodegeneration Dopaminergic Wild type General Medicine Middle Aged medicine.disease Phenotype Mitochondria Rats nervous system diseases Cell biology Substantia Nigra medicine.anatomical_structure nervous system health occupations Synuclein Female 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics. 30:247-264 |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Beta (ß)-synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related alpha (α)-synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in central nervous system (CNS) neurons in vitro and in vivo, albeit at a slower pace as compared with α-Syn. Here, we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of dementia with Lewy bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but it has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but it does not aggravate neurodegeneration. ß-Syn wild type (WT), V70M and P123H formed proteinase K-resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared with α-Syn. Under cell-free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared with WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, which are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn and is thus likely to be directly involved into the etiology of DLB. Overall, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn. |
| Databáze: | OpenAIRE |
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