Fig. 8.

Working model for uN2CpolyG-induced mitochondrial dysfunction and progressive neurodegeneration. In this study, the CGG repeat expansion of NOTCH2NLC is translated into toxic uN2CpolyG protein, which leads to intranuclear inclusion formation and progressive neurodegeneration in multiple systems of a Drosophila model. The uN2CpolyG protein is associated with mitochondria and interacts with a mitochondrial RNA binding protein, LRPPRC, which may lead to mitochondrial RNA (mtRNA) instability and reducing mitochondrial OXPHOS complex-related RNA expression. Eventually, down-regulation of complex I activity, reduced OCRs, and decreased ATP synthesis contribute to neuronal and muscle cell degeneration. The use of IDB may reverse mitochondrial damage and alleviate neurodegenerative phenotypes in a transgenic fly model.