Identifying the role of miRNAs in the development of neuromuscular disorders

• Applicant: Professorin Dr. Halyna Shcherbata
• Subject Area: Developmental Neurobiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521749003

In Germany alone, more than 150000 people suffer from neuromuscular disorders. Many forms of congenital muscular dystrophies are associated with abnormalities in the evolutionary conserved Dystrophin glycoprotein complex (DGC) that links the extracellular matrix to the cytoskeleton. Patients experience progressive muscle deterioration and debilitation; death usually occurs due to cardiac and respiratory failure and no cure exists to treat these fatal disorders. Importantly, DGC levels significantly decline upon aging or due to various diseases, causing muscle wasting, cachexia and muscle atrophy. In addition, to muscle degeneration, abnormal expression of the key DGC component, the extracellular matrix receptor Dystroglycan causes lissencephaly type II or cobblestone brain, which is characterized by irregular borders due to overmigration of neurons and glial cells beyond the external basement membrane. Our current understanding of mechanisms reducing DGC content is fundamentally limited due to lack of information on regulation of the DGC upon aging or in disease. The DGC consists of multiple subunits that can be differentially regulated by gene expression or post-translational regulation by protein breakdown. In this proposal, we expect to dissect the mechanisms of post-transcriptional regulation of mRNA stability of various DGC components by miRNAs. miRNAs have emerged as important gene expression regulators upon stress and disease. Moreover, miRNA expression profile is altered in muscular dystrophy patients. Currently, miRNAs have been developed as important diagnostic markers for multiple human disorders, including muscular dystrophies and neurodegenerative diseases; however, the exact roles of miRNAs in regulation of DGC integrity in aged or diseased patients are unknown.Analysis of DGC regulation in vertebrates is time-consuming and expensive, and given the evolutionary conservation of DGC components in Drosophila, research can be done using the fly model system. Previously, we have developed Drosophila models for muscular dystrophy and lissencephaly type II and identified several miRNAs regulating the DGC during development. Now we propose to take advantage of the powerful genetic and molecular technology available in Drosophila system in order to develop and implement a novel and multi-disciplinary approach for the identification, characterization and manipulation of the miRNAs essential for fine-tuning of the DGC expression in aged and diseased muscles and brains.Understanding of the post-transcriptional miRNA-based targeting of DGC subunits in Drosophila would give an insight into the DGC regulation under normal and stress conditions in humans. This study will provide new knowledge of the mechanisms that contribute to dystrophic muscle degeneration and facilitate development of alternative pathways for treatment of these fatal neuromuscular disorders using miRNAs as therapeutic agents.

• DFG Programme: Research Grants