Hallmark molecular and pathological features of POLG disease are recapitulated in cerebral organoids

Abstract

AbstractIn our research, we developed a 3D brain organoid model to study POLG-related encephalopathy, a mitochondrial disease stemming fromPOLGgene mutations. We utilized induced pluripotent stem cells (iPSCs) derived from patients with these mutations to generate cortical organoids, which exhibited typical POLG disease features, such as altered morphology, neuronal loss, and mtDNA depletion. We also identified significant dysregulation in pathways crucial for neuronal development and function, alongside upregulated NOTCH and JAK-STAT signaling pathways. Metformin treatment ameliorated many of these abnormalities, except for the persistent affliction of inhibitory DA GLU neurons. This novel model effectively mirrors both the molecular and pathological attributes of POLG disease, providing a valuable tool for mechanistic understanding and therapeutic screening for POLG-related disorders and other conditions characterized by compromised neuronal mtDNA maintenance and complex I deficiency.HighlightsWe have successfully developed cortical organoid model that represents POLG-related disease.This model effectively replicates both histological and molecular signatures seen in the brains of patients.The cortical organoid model displays a range of features common in POLG-related disease, including neurodegeneration, mtDNA depletion, and neuronal complex I deficiency.The use of metformin supplementation in this model improved mitochondria protein and reduced cell death.