Journal Article

DZNE-2026-00944

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png C9orf72-associated and sporadic FTD patient iPSC-microglia show differences in phagocytosis and gene expression.

Rostalski, H. ; Hietanen, T. ; Hoffmann, D. ; Heikkinen, S. ; Huber, N. ; Dhingra, A.DZNE* ; Rodriguez-Nieto, S.DZNE* ; Kuulasmaa, T. ; Ohtonen, S. ; Jäntti, H. ; Pekkala, V. ; Leskelä, S. ; Mäkinen, P. ; Katisko, K. ; Hartikainen, P. ; Lehtonen, Š. ; Solje, E. ; Koistinaho, J. ; Malm, T. ; Portaankorva, A. M. ; Natunen, T. ; Martiskainen, H. ; Takalo, M. ; Hiltunen, M. ; Haapasalo, A.

2026
Cell Press Maryland Heights, MO

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Please use a persistent id in citations: doi:10.1016/j.stemcr.2026.103026

Abstract: 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.

Keyword(s): Humans (MeSH) ; C9orf72 Protein: genetics (MeSH) ; C9orf72 Protein: metabolism (MeSH) ; Phagocytosis: genetics (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: pathology (MeSH) ; Frontotemporal Dementia: metabolism (MeSH) ; Microglia: metabolism (MeSH) ; Microglia: pathology (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Induced Pluripotent Stem Cells: cytology (MeSH) ; Female (MeSH) ; Male (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Gene Expression Regulation (MeSH) ; ALS ; C9orf72 hexanucleotide repeat expansion ; FTD ; RNA sequencing ; microglia ; phagocytosis ; C9orf72 Protein ; C9orf72 protein, human

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Contributing Institute(s):

1. Genome Biology of Neurodegenerative Diseases (AG Heutink)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

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