Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung


  • Sukhleen Kour - , University of Pittsburgh (Autor:in)
  • Tyler Fortuna - , University of Pittsburgh (Autor:in)
  • Eric N. Anderson - , University of Pittsburgh (Autor:in)
  • Darilang Mawrie - , University of Pittsburgh (Autor:in)
  • Jessica Bilstein - , Technische Universität Dresden (Autor:in)
  • Ramakrishnan Sivasubramanian - , Technische Universität Dresden (Autor:in)
  • Caroline Ward - , University of Pittsburgh (Autor:in)
  • Rishit Roy - , University of Pittsburgh (Autor:in)
  • Dhivyaa Rajasundaram - , University of Pittsburgh (Autor:in)
  • Jared Sterneckert - , Professur für iPS Zellen und neurodegenerative Erkrankungen, Center for Regenerative Therapies Dresden (CRTD), Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Udai Bhan Pandey - , University of Pittsburgh (Autor:in)


Mutations in the Fused in Sarcoma (FUS) gene cause the familial and progressive form of amyotrophic lateral sclerosis (ALS). FUS is a nuclear RNA-binding protein involved in RNA processing and the biogenesis of a specific set of microRNAs. Here we report that Drosha and two previously uncharacterized Drosha-dependent miRNAs are strong modulators of FUS expression and prevent the cytoplasmic segregation of insoluble mutant FUS in vivo. We demonstrate that depletion of Drosha mitigates FUS-mediated degeneration, survival and motor defects in Drosophila. Mutant FUS strongly interacts with Drosha and causes its cytoplasmic mis-localization into the insoluble FUS inclusions. Reduction in Drosha levels increases the solubility of mutant FUS. Interestingly, we found two Drosha dependent microRNAs, miR-378i and miR-6832-5p, which differentially regulate the expression, solubility and cytoplasmic aggregation of mutant FUS in iPSC neurons and mammalian cells. More importantly, we report different modes of action of these miRNAs against mutant FUS. Whereas miR-378i may regulate mutant FUS inclusions by preventing G3BP-mediated stress granule formation, miR-6832-5p may affect FUS expression via other proteins or pathways. Overall, our research reveals a possible association between ALS-linked FUS mutations and the Drosha-dependent miRNA regulatory circuit, as well as a useful perspective on potential ALS treatment via microRNAs.


Seiten (von - bis)11258-11276
FachzeitschriftNucleic acids research
Jahrgang51 (2023)
PublikationsstatusVeröffentlicht - 4 Okt. 2023

Externe IDs

PubMed 37791873
ORCID /0000-0002-7688-3124/work/155840531


ASJC Scopus Sachgebiete