Toward novel functions of C9orf72 as ribosome modulator and translation regulator in axons of spinal motoneurons

• Applicant: Mehri Moradi, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537594920

The hexanucleotide repeat expansions in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The pathological mechanisms of C9ORF72-caused ALS/FTD seem to enclose both loss and toxic gain of functions. Despite emerging evidence about loss of function mechanisms, the cellular and physiological roles of C9ORF72 and their importance for ALS pathogenesis remain poorly investigated. Our preliminary data from C9ORF72 proteomics in motoneurons as well as co-IP experiments with NSC34 cells reveal a significant interaction between C9orf72 and ribosomes. Importantly, these interactions are critical for the translation elongation phase, since shRNA-mediated targeting of C9orf72 significantly reduces the translation capacity in cultured motoneurons, in particular in axons. The goal of this research project is to unravel whether C9orf72 interaction with ribosomes implies a function of C9orf72 in translation regulation in motoneurons, and to characterize the pathological relevance of this interaction on axon degeneration in ALS. The outcome of this proposed work should provide new insights into the loss of function mechanisms using an appropriate system for the investigation of ALS axonopathy and neurodegeneration.

• DFG Programme: Research Grants