Elucidation of the Molecular Mechanism Underlying Aberrant Formation of RNA Granules in Neurons of ALS Patients and Its Regulation

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by progressive muscle atrophy throughout the body. In nearly all ALS patients, abnormal accumulation of the RNA-binding protein TDP-43 is observed in degenerating motor neurons. We have found that RNA-binding proteins such as TDP-43 and FUS are concentrated in GEM bodies, where they contribute to the integrity of the spliceosome machinery involved in pre-RNA splicing. Additionally, the most common cause of ALS, repeat expansion in the C9orf72 gene, triggers abnormal repeat-associated non-AUG (RAN) translation, leading to the accumulation of neurotoxic dipeptide repeat (DPR) proteins. We have identified that these DPR proteins may inhibit GEM body formation and contribute to ALS pathology. Furthermore, therapeutic approaches to suppress RAN translation using dCas13 technology are under development, offering promising new strategies to address abnormalities in RNA metabolism in ALS.