类有机物
诱导多能干细胞
疾病
线粒体DNA
线粒体
神经科学
突变
生物
细胞生物学
病理
医学
遗传学
胚胎干细胞
基因
作者
Anbin Chen,Tsering Yangzom,Yu Hong,B. Lundberg,Gareth J. Sullivan,Charalampos Tzoulis,Laurence A. Bindoff,Kristina Xiao Liang
标识
DOI:10.1002/advs.202307136
摘要
In this research, a 3D brain organoid model is developed to study POLG-related encephalopathy, a mitochondrial disease stemming from POLG mutations. Induced pluripotent stem cells (iPSCs) derived from patients with these mutations is utilized to generate cortical organoids, which exhibited typical features of the diseases with POLG mutations, such as altered morphology, neuronal loss, and mitochondiral DNA (mtDNA) depletion. Significant dysregulation is also identified 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 dopamine-glutamate (DA GLU) neurons. This novel model effectively mirrors both the molecular and pathological attributes of diseases with POLG mutations, 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.
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