Replication of multiple system atrophy prions in primary astrocyte cultures from transgenic mice expressing human α-synuclein
| Autor: | Kurt Giles, George A. Carlson, Zuzana Krejciova, Stanley B. Prusiner |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cytoplasmic inclusion animal diseases Neurodegenerative lcsh:RC346-429 Transgenic Mice chemistry.chemical_compound 0302 clinical medicine 2.1 Biological and endogenous factors Aetiology Cells Cultured Inclusion Bodies α-Synuclein Cultured Neurodegeneration Recombinant Proteins Cell biology medicine.anatomical_structure Neurological Proteinopathies alpha-Synuclein Prion Thioflavin Astrocyte Genetically modified mouse Prions Dendritic Spines Cells Clinical Sciences Hyperphosphorylation Mice Transgenic Biology Pathology and Forensic Medicine 03 medical and health sciences Cellular and Molecular Neuroscience Rare Diseases MSA mental disorders Acquired Cognitive Impairment medicine Animals Humans lcsh:Neurology. Diseases of the nervous system Tropism Synucleinopathies Research Neurosciences Multiple System Atrophy Synuclein medicine.disease Brain Disorders nervous system diseases 030104 developmental biology nervous system chemistry Astrocytes Dementia Biochemistry and Cell Biology Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Krejciova, Zuzana; Carlson, George A; Giles, Kurt; & Prusiner, Stanley B. (2019). Replication of multiple system atrophy prions in primary astrocyte cultures from transgenic mice expressing human α-synuclein.. Acta neuropathologica communications, 7(1), 81. doi: 10.1186/s40478-019-0703-9. UCSF: Retrieved from: http://www.escholarship.org/uc/item/36t5x4j0 Acta neuropathologica communications, vol 7, iss 1 Acta Neuropathologica Communications Acta Neuropathologica Communications, Vol 7, Iss 1, Pp 1-19 (2019) |
| ISSN: | 2051-5960 |
| DOI: | 10.1186/s40478-019-0703-9 |
| Popis: | Glial cytoplasmic inclusions (GCIs) containing aggregated and hyperphosphorylated α-synuclein are the signature neuropathological hallmark of multiple system atrophy (MSA). Native α-synuclein can adopt a prion conformation that self-propagates and spreads throughout the brain ultimately resulting in neurodegeneration. A growing body of evidence argues that, in addition to oligodendrocytes, astrocytes contain α-synuclein inclusions in MSA and other α-synucleinopathies at advanced stages of disease. To study the role of astrocytes in MSA, we added MSA brain homogenate to primary cultures of astrocytes from transgenic (Tg) mouse lines expressing human α-synuclein. Astrocytes from four Tg lines, expressing either wild-type or mutant (A53T or A30P) human α-synuclein, propagated and accumulated α-synuclein prions. Furthermore, we found that MSA-infected astrocytes formed two morphologically distinct α-synuclein inclusions: filamentous and granular. Both types of cytoplasmic inclusions shared several features characteristic of α-synuclein inclusions in synucleinopathies: hyperphosphorylation preceded by aggregation, ubiquitination, thioflavin S–positivity, and co-localization with p62. Our findings demonstrate that human α-synuclein forms distinct inclusion morphologies and propagates within cultured Tg astrocytes exposed to MSA prions, indicating that α-synuclein expression determines the tropism of inclusion formation in certain cells. Thus, our work may prove useful in elucidating the role of astrocytes in the pathogenic mechanisms that feature in neurodegeneration caused by MSA prions. Electronic supplementary material The online version of this article (10.1186/s40478-019-0703-9) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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