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Human iPSC-derived microglia carrying the LRRK2-G2019S mutation show a Parkinson's disease related transcriptional

Sohvi Ohtonen1, Luca Giudice2, Henna Jäntti2,3,4

  • 1A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. sohvi.ohtonen@uef.fi.

Scientific Reports
|December 13, 2023
PubMed

Insights

The LRRK2-G2019S mutation in Parkinson's disease (PD) alters human microglia-like cells (iMGLs). These LRRK2-G2019S iMGLs show transcriptional overlap with microglia from PD brains, validating their use as a PD research model.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • The LRRK2-G2019S mutation is a common genetic factor associated with Parkinson's disease (PD).
  • Microglia, the immune cells of the brain, are implicated in PD pathogenesis, but their specific response to LRRK2 mutations is not fully understood.
  • The transcriptional profile of human induced pluripotent stem cell-derived microglia-like cells (iMGLs) carrying the LRRK2-G2019S mutation and its correlation with idiopathic PD microglia remain largely unknown.

Purpose of the Study:

  • To investigate the impact of the LRRK2-G2019S mutation on the transcriptional profile of human iMGLs.
  • To compare the transcriptional signature of LRRK2-G2019S iMGLs with microglia from idiopathic Parkinson's disease (PD) brains.
  • To establish LRRK2-G2019S iMGLs as a relevant in vitro model for studying PD-related microglial changes.

Main Methods:

  • Generation of human induced pluripotent stem cell-derived microglia-like cells (iMGLs) carrying the LRRK2-G2019S mutation.
  • Analysis of iMGL mitochondrial respiration, phagocytosis, and cytokine secretion.
  • Transcriptional profiling of iMGLs and comparison with microglial transcriptomes from post-mortem idiopathic PD brains.

Main Results:

  • LRRK2-G2019S iMGLs exhibited subtle, donor-dependent alterations in mitochondrial respiration, phagocytosis, and cytokine secretion.
  • A subset of microglia in idiopathic PD midbrains displayed a transcriptional signature overlapping with the LRRK2-G2019S iMGLs.
  • The study successfully recapitulated aspects of the transcriptional signature of human idiopathic PD midbrain microglia in LRRK2-G2019S iMGLs.

Conclusions:

  • LRRK2-G2019S iMGLs serve as a valuable in vitro model for investigating Parkinson's disease mechanisms.
  • The findings highlight a transcriptional overlap between LRRK2-mutant iMGLs and microglia found in idiopathic PD brains.
  • This study provides insights into how a common PD-associated mutation affects human microglial function and gene expression.

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