SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration

Fortuna, Tyler R.; Kour, Sukhleen; Chimata, Anuradha Venkatakrishnan; Muiños-Bühl, Anixa; Anderson, Eric N.; Nelson, Christine; Ward, Caroline; Chauhan, O. P.; O’Brien, Casey P.; Rajasundaram, Dhivyaa; Rajan, Deepa; Wirth, Brunhilde; Singh, Amit; Pandey, Udai Bhan

doi:10.1007/s00401-023-02607-8

Cited by 5 publications

(1 citation statement)

References 74 publications

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“…In flies, RNA was isolated using TRizol (Ambion; 15596026) as previously described ( 17 , 43 , 45 , 46 ). Around nine fly heads were used for RNA extraction, and gene expression was normalized with tubulin.…”

Section: Methodsmentioning

confidence: 99%

Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo

Kour,

Fortuna,

Anderson

et al. 2023

Nucleic Acids Research

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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.

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