Stem cell reports · 2026
C9orf72-associated and sporadic FTD patient iPSC-microglia show differences in phagocytosis and gene expression.
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Rostalski Hannah, Hietanen Tomi, Hoffmann Dorit, Heikkinen Sami, Huber Nadine, Dhingra Ashutosh, Rodriguez-Nieto Salvador, Kuulasmaa Teemu, Ohtonen Sohvi, Jäntti Henna, Pekkala Viivi, Leskelä Stina, Mäkinen Petra, Katisko Kasper, Hartikainen Päivi, Lehtonen Šárka, Solje Eino, Koistinaho Jari, Malm Tarja, Portaankorva Anne M, Natunen Teemu, Martiskainen Henna, Takalo Mari, Hiltunen Mikko, Haapasalo Annakaisa
Аннотация
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.