| First Author | Krejciova Z | Year | 2019 |
| Journal | Acta Neuropathol Commun | Volume | 7 |
| Issue | 1 | Pages | 81 |
| PubMed ID | 31109379 | Mgi Jnum | J:339104 |
| Mgi Id | MGI:6782007 | Doi | 10.1186/s40478-019-0703-9 |
| Citation | Krejciova Z, et al. (2019) Replication of multiple system atrophy prions in primary astrocyte cultures from transgenic mice expressing human alpha-synuclein. Acta Neuropathol Commun 7(1):81 |
| abstractText | Glial cytoplasmic inclusions (GCIs) containing aggregated and hyperphosphorylated alpha-synuclein are the signature neuropathological hallmark of multiple system atrophy (MSA). Native alpha-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 alpha-synuclein inclusions in MSA and other alpha-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 alpha-synuclein. Astrocytes from four Tg lines, expressing either wild-type or mutant (A53T or A30P) human alpha-synuclein, propagated and accumulated alpha-synuclein prions. Furthermore, we found that MSA-infected astrocytes formed two morphologically distinct alpha-synuclein inclusions: filamentous and granular. Both types of cytoplasmic inclusions shared several features characteristic of alpha-synuclein inclusions in synucleinopathies: hyperphosphorylation preceded by aggregation, ubiquitination, thioflavin S-positivity, and co-localization with p62. Our findings demonstrate that human alpha-synuclein forms distinct inclusion morphologies and propagates within cultured Tg astrocytes exposed to MSA prions, indicating that alpha-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. |
