期刊
FRONTIERS IN CELLULAR NEUROSCIENCE
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fncel.2019.00480
关键词
amyotrophic lateral sclerosis; induced pluripotent stem cells; FUS; rabies virus; HIV-1; Zika virus
资金
- Deutsche Forschungsgemeinschaft (DFG)
- CRTD part of the TUD
- DFG Research Center [DFG FZT 111]
- DFG Cluster of Excellence [DFG EXC 168]
- European Union's Horizon 2020 Research and Innovation Program [643417]
- Bundesministerium fur Bildung und Forschung [01ED1601B]
- Bundesministerium fur Bildung und Forschung, Germany
- Ministry of Health, Israel
- Ministero dell'Istruzione dell'Universita e della Ricerca, Italy
- Swedish Research Council, Sweden
- Swiss National Science Foundation, Switzerland
- Hans und Ilse Breuer Stiftung
- Canadian Institutes of Health Research [MOP-56974]
Amyotrophic lateral sclerosis (ALS) arises from an interplay of genetic mutations and environmental factors. ssRNA viruses are possible ALS risk factors, but testing their interaction with mutations such as in FUS, which encodes an RNA-binding protein, has been difficult due to the lack of a human disease model. Here, we use isogenic induced pluripotent stem cell (iPSC)-derived spinal neurons (SNs) to investigate the interaction between ssRNA viruses and mutant FUS. We find that rabies virus (RABV) spreads ALS phenotypes, including the formation of stress granules (SGs) with aberrant composition due to increased levels of FUS protein, as well as neurodegeneration and reduced restriction activity by FUS mutations. Consistent with this, iPSC-derived SNs harboring mutant FUS are more sensitive to human immunodeficiency virus (HIV-1) and Zika viruses (ZIKV). We demonstrate that RABV and HIV-1 exacerbate cytoplasmic mislocalization of FUS. Our results demonstrate that viral infections worsen ALS pathology in SNs with genetic risk factors, suggesting a novel role for viruses in modulating patient phenotypes.
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