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Andreas Heuer

Andreas Heuer

Research team manager

Andreas Heuer

Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene


  • Margarita Chumarina
  • Kaspar Russ
  • Carla Azevedo
  • Andreas Heuer
  • Maria Pihl
  • Anna Collin
  • Eleonor Åsander Frostner
  • Eskil Elmer
  • Poul Hyttel
  • Graziella Cappelletti
  • Michela Zini
  • Stefano Goldwurm
  • Laurent Roybon

Summary, in English

Variations in the POLG1 gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma, have recently been associated with Parkinson's disease (PD), especially in patients diagnosed with progressive external ophthalmoplegia (PEO). However, the majority of the studies reporting this association mainly focused on the genetic identification of the variation in POLG1 in PD patient primary cells, and determination of mitochondrial DNA copy number, providing little information about the cellular alterations existing in patient brain cells, in particular dopaminergic neurons. Therefore, through the use of induced pluripotent stem cells (iPSCs), we assessed cellular alterations in novel p.Q811R POLG1 (POLG1Q811R) variant midbrain dopaminergic neuron-containing spheroids (MDNS) from a female patient who developed early-onset PD, and compared them to cultures derived from a healthy control of the same gender. Both POLG1 variant and control MDNS contained functional midbrain regionalized TH/FOXA2-positive dopaminergic neurons, capable of releasing dopamine. Western blot analysis identified the presence of high molecular weight oligomeric alpha-synuclein in POLG1Q811R MDNS compared to control cultures. In order to assess POLG1Q811R-related cellular alterations within the MDNS, we applied mass-spectrometry based quantitative proteomic analysis. In total, 6749 proteins were identified, with 61 significantly differentially expressed between POLG1Q811R and control samples. Pro-And anti-inflammatory signaling and pathways involved in energy metabolism were altered. Notably, increased glycolysis in POLG1Q811R MDNS was suggested by the increase in PFKM and LDHA levels and confirmed using functional analysis of glycolytic rate and oxygen consumption levels. Our results validate the use of iPSCs to assess cellular alterations in relation to PD pathogenesis, in a unique PD patient carrying a novel p.Q811R variation in POLG1, and identify several altered pathways that may be relevant to PD pathogenesis.


  • IPSC Laboratory for CNS Disease Modeling
  • MultiPark: Multidisciplinary research focused on Parkinson´s disease
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • Behavioural Neuroscience Laboratory
  • Division of Clinical Genetics
  • Mitochondrial Medicine

Publishing year





Acta Neuropathologica Communications





Document type

Journal article


BioMed Central (BMC)


  • Neurosciences
  • Cell and Molecular Biology


  • Alpha-synuclein
  • Glycolysis
  • iPSCs
  • MAO-B
  • Midbrain spheroids
  • Parkinson's disease
  • POLG1
  • Proteomics



Research group

  • IPSC Laboratory for CNS Disease Modeling
  • Behavioural Neuroscience Laboratory
  • Mitochondrial Medicine


  • ISSN: 2051-5960