New Insights into ALS Pathophysiology: Drosha and miRNA’s Role in Modulating FUS-mediated Neurodegeneration

New research from the Pandey Laboratory, led by Udai B. Pandey, PhD, in the Division of Child Neurology at UPMC Children’s Hospital of Pittsburgh has found a correlation between mutations in the Fused in Sarcoma (FUS) gene and the familial form of amyotrophic lateral sclerosis (ALS).

The study provides new details on ALS pathogenesis and potential therapeutic approaches. The FUS gene, which is involved in RNA processing and microRNA (miRNA) biogenesis, has been linked to neurodegenerative processes characterizing ALS.

The study was published in October 2023 in the journal Nucleic Acids Research.

Study Details and Key Findings

Dr. Pandey’s teams research found that Drosha, a core ribonuclease in the miRNA processing pathway, to be an important modulator of FUS expression and solubility. Their study demonstrated that reducing Drosha levels curtails the FUS-mediated degeneration seen in models, which points to Drosha's suppressive effect on FUS-mediated neurotoxicity.

The study identified two Drosha-dependent miRNAs, miR-378i and miR-6832–5p, which exert contrasting influences on the expression and aggregation of mutant FUS proteins. miR-378i appears to inhibit the formation of stress granules associated with mutant FUS proteins, preventing pathological aggregation. On the other hand, miR-6832–5p functions through alternate pathways.

“Our team’s research has uncovered the complex interrelationship between Drosha, miRNAs, and the FUS gene in the pathology of ALS,” says Dr. Pandey. “Drosha's modulation of FUS levels, combined with the differential regulation exerted the miRNAs, presents a multifaceted molecular landscape, and could provide for future research into therapeutic modulation of the mechanisms at play.”

Dr. Pandey’s team’s study highlights the roles of RNA processing components in neurodegenerative disease and increasing the understanding of ALS's molecular mechanisms.

The findings that Drosha and the two miRNAs can mitigate the neurodegenerative effects mediated by FUS mutations offers promising directions for future ALS research.

By targeting these newly identified molecular interactions, it might be possible to develop innovative interventions to modulate FUS-mediated pathologies in ALS as a means toward improving the management of this complex and devastating neurodegenerative disorder.

Reference

Kour S, Fortuna T, Anderson EN, Mawrie D, Bellmann J, Sivasubramanian R, Ward C, Roy R, Rajasundaram D, Sterneckert J, Pandey UB. Drosha-Dependent microRNAs Modulate FUS-Mediated Neurodegeneration In Vivo. Nucleic Acids Res. 2023 Oct 4; gkad774. Online ahead of print.