Human iPSC-derived microglia carrying the LRRK2-G2019S mutation show a Parkinson’s disease related transcriptional profile and function
Sohvi Ohtonen, Luca Giudice, Henna Jäntti, Mohammad Feroze Fazaludeen, Anastasia Shakirzyanova, Mireia Gómez‐Budia, Nelli‐Noora Välimäki, Jonna Niskanen, Nea Korvenlaita, Ilkka Fagerlund, Jari Koıstınaho, Mahmood Amiry‐Moghaddam, Ekaterina Savchenko, Laurent Roybon, Šárka Lehtonen, Paula Korhonen, Tarja Malm
Abstract
LRRK2-G2019S is one of the most common Parkinson's disease (PD)-associated mutations and has been shown to alter microglial functionality. However, the impact of LRRK2-G2019S on transcriptional profile of human induced pluripotent stem cell-derived microglia-like cells (iMGLs) and how it corresponds to microglia in idiopathic PD brain is not known. Here we demonstrate that LRRK2-G2019S carrying iMGL recapitulate aspects of the transcriptional signature of human idiopathic PD midbrain microglia. LRRK2-G2019S induced subtle and donor-dependent alterations in iMGL mitochondrial respiration, phagocytosis and cytokine secretion. Investigation of microglial transcriptional state in the midbrains of PD patients revealed a subset of microglia with a transcriptional overlap between the in vitro PD-iMGL and human midbrain PD microglia. We conclude that LRRK2-G2019S iMGL serve as a model to study PD-related effects in human microglia.