Hannah Rostalski, Tomi Hietanen, Dorit Hoffmann, Sami Heikkinen, Nadine Huber, Ashutosh Dhingra, Salvador Rodriguez-Nieto, Teemu Kuulasmaa, Sohvi Ohtonen, Henna Jäntti, Viivi Pekkala, Stina Leskelä, Petra Mäkinen, Kasper Katisko, Päivi Hartikainen, Šárka Lehtonen, Eino Solje, Jari Koistinaho, Tarja Malm, Anne M Portaankorva, Teemu Natunen, Henna Martiskainen, Mari Takalo, Mikko Hiltunen, Annakaisa Haapasalo
C9orf72 hexanucleotide repeat expansion (C9-HRE) is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). However, approximately half of the FTD patients are sporadic without a clear genetic background. To compare characteristics of microglia from different FTD subtypes, we generated induced pluripotent stem cell-derived microglia (iMG) from sporadic and C9-HRE-carrying behavioral variant FTD (bvFTD) patients and healthy controls. C9-HRE iMG displayed C9-HRE-associated RNA foci and dipeptide repeat proteins. All bvFTD iMG had fewer LAMP2-A-positive vesicles compared to control iMG. Additionally, C9-HRE iMG showed significantly increased LC3BII/I conversion after bafilomycin A1 treatment and altered phagocytic activity. The gene expression profile of C9-HRE iMG only modestly differed from the control iMG, but was greatly different from the sporadic bvFTD patient iMG. Our data show alterations in phagocytic and autophagosomal/lysosomal pathways and gene expression profiles between C9-HRE and sporadic bvFTD iMG for the first time.