Disease‐specific phenotypes in iPSC‐derived neural stem cells with POLG mutations

@article{Liang2020DiseasespecificPI,
  title={Disease‐specific phenotypes in iPSC‐derived neural stem cells with POLG mutations},
  author={Kristina Xiao Liang and Cecilie Katrin Kristiansen and Sepideh Mostafavi and Guro Hel{\'e}n Vatne and Gina Alien Zantingh and Atefeh Kianian and Charalampos Tzoulis and Lena Elise H{\o}yland and Mathias Ziegler and Roberto Megias Perez and Jessica Furriol and Zhuoyuan Zhang and Novin Balafkan and Yu Hong and Richard Siller and Gareth John Sullivan and Laurence A. Bindoff},
  journal={EMBO Molecular Medicine},
  year={2020},
  volume={12}
}
Mutations in POLG disrupt mtDNA replication and cause devastating diseases often with neurological phenotypes. Defining disease mechanisms has been hampered by limited access to human tissues, particularly neurons. Using patient cells carrying POLG mutations, we generated iPSCs and then neural stem cells. These neural precursors manifested a phenotype that faithfully replicated the molecular and biochemical changes found in patient post‐mortem brain tissue. We confirmed the same loss of mtDNA… 
POLG mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via SIRT3/AMPK pathway inhibition
ABSTRACT We showed previously that POLG mutations cause major changes in mitochondrial function, including loss of mitochondrial respiratory chain (MRC) complex I, mitochondrial DNA (mtDNA) depletion
Stem cell derived astrocytes with POLG mutations and mitochondrial dysfunction including abnormal NAD+ metabolism is toxic for neurons
TLDR
These studies provide a robust astroglia-neuronal interaction model for future investigation of mitochondrial involvement in neurogenesis and neurodegenerative diseases and demonstrate that mitochondrial dysfunction caused by POLG mutations leads not only to intrinsic defects in energy metabolism affecting both neurons and astrocytes, but also to neurotoxic damage driven by astroCytes.
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