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Published on: April 24, 2021
Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo
Sukhleen Kour1, Tyler Fortuna1, Eric N Anderson1
1Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.
Abstract:
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.
Insights
Mutations in the Fused in Sarcoma (FUS) gene cause amyotrophic lateral sclerosis (ALS). This study reveals Drosha and specific microRNAs regulate FUS, offering potential new ALS treatments.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- Mutations in the Fused in Sarcoma (FUS) gene are linked to familial amyotrophic lateral sclerosis (ALS).
- FUS protein is crucial for RNA processing and microRNA biogenesis.
- Understanding FUS regulation is key to developing ALS therapies.
Purpose of the Study:
- To investigate the role of Drosha and its dependent microRNAs in modulating FUS expression and aggregation.
- To explore the therapeutic potential of targeting the Drosha-microRNA pathway for ALS treatment.
Main Methods:
- Investigated FUS protein interactions with Drosha in cellular and animal models.
- Assessed the impact of Drosha depletion on FUS-mediated neurodegeneration in Drosophila.
- Analyzed the regulatory effects of specific microRNAs (miR-378i and miR-6832-5p) on mutant FUS in iPSC neurons and mammalian cells.
Main Results:
- Drosha and two novel Drosha-dependent microRNAs significantly modulate FUS expression and prevent mutant FUS cytoplasmic aggregation.
- Depletion of Drosha mitigates FUS-induced degeneration and motor deficits in Drosophila.
- Mutant FUS interacts with and causes cytoplasmic mis-localization of Drosha, which is reversed by reducing Drosha levels.
- miR-378i and miR-6832-5p differentially regulate FUS expression, solubility, and aggregation, with distinct mechanisms of action.
Conclusions:
- A link exists between ALS-associated FUS mutations and the Drosha-dependent microRNA regulatory circuit.
- Targeting Drosha-dependent microRNAs presents a promising therapeutic strategy for ALS.
