Viral Infections Exacerbate FUS-ALS Phenotypes in iPSC-Derived Spinal Neurons in a Virus Species-Specific Manner

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Jessica Bellmann - , Technische Universität Dresden (Autor:in)
  • Anne Monette - , McGill University (Autor:in)
  • Vadreenath Tripathy - , Technische Universität Dresden (Autor:in)
  • Anna Sójka - , Technische Universität Dresden (Autor:in)
  • Masin Abo-Rady - , Technische Universität Dresden (Autor:in)
  • Antje Janosh - , Max Planck Institute of Molecular Cell Biology and Genetics (Autor:in)
  • Rajat Bhatnagar - , Verge Genomics (Autor:in)
  • Marc Bickle - , Max Planck Institute of Molecular Cell Biology and Genetics (Autor:in)
  • Andrew J. Mouland - , McGill University (Autor:in)
  • Jared Sterneckert - , IPS Zellen und neurodegenerative Erkrankungen (NFoG) (Autor:in)

Abstract

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.

Details

OriginalspracheEnglisch
Aufsatznummer480
FachzeitschriftFrontiers in cellular neuroscience
Jahrgang13
PublikationsstatusVeröffentlicht - 22 Okt. 2019
Peer-Review-StatusJa

Externe IDs

ORCID /0000-0002-7688-3124/work/142250021

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • amyotrophic lateral sclerosis, FUS, HIV-1, induced pluripotent stem cells, rabies virus, Zika virus

Bibliotheksschlagworte