Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3

Abinaya Chandrasekaran, Katarina Stoklund Dittlau, Giulia I Corsi, Henriette Haukedal, Nadezhda T Doncheva, Sarayu Ramakrishna, Sheetal Ambardar, Claudia Salcedo, Sissel I Schmidt, Yu Zhang, Susanna Cirera, Maria Pihl, Benjamin Schmid, Troels Tolstrup Nielsen, Jørgen E Nielsen, Miriam Kolko, Julianna Kobolák, András Dinnyés, Poul Hyttel, Dasaradhi PalakodetiJan Gorodkin, Ravi S Muddashetty, Morten Meyer, Blanca I Aldana, Kristine K Freude

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Abstract

Frontotemporal dementia type 3 (FTD3), caused by a point mutation in the charged multivesicular body protein 2B (CHMP2B), affects mitochondrial ultrastructure and the endolysosomal pathway in neurons. To dissect the astrocyte-specific impact of mutant CHMP2B expression, we generated astrocytes from human induced pluripotent stem cells (hiPSCs) and confirmed our findings in CHMP2B mutant mice. Our data provide mechanistic insights into how defective autophagy causes perturbed mitochondrial dynamics with impaired glycolysis, increased reactive oxygen species, and elongated mitochondrial morphology, indicating increased mitochondrial fusion in FTD3 astrocytes. This shift in astrocyte homeostasis triggers a reactive astrocyte phenotype and increased release of toxic cytokines, which accumulate in nuclear factor kappa b (NF-κB) pathway activation with increased production of CHF, LCN2, and C3 causing neurodegeneration.

Original languageEnglish
JournalStem Cell Reports
Volume16
Issue number11
Pages (from-to)2736-2751
ISSN2213-6711
DOIs
Publication statusPublished - 9. Nov 2021

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