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

Chandrasekaran, Abinaya ; Dittlau, Katarina Stoklund ; Corsi, Giulia I. ; Haukedal, Henriette ; Doncheva, Nadezhda T. ; Ramakrishna, Sarayu ; Ambardar, Sheetal ; Salcedo, Claudia ; Schmidt, Sissel I. and Zhang, Yu LU orcid , et al. (2021) In Stem Cell Reports p.2736-2751
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
autophagy, CHMP2B, complement 3, cytokines, FTD3, hiPSC-derived astrocytes, mitochondria, NF-kB, reactive astrocytes
in
Stem Cell Reports
pages
16 pages
publisher
Cell Press
external identifiers
  • pmid:34678206
  • scopus:85123228913
ISSN
2213-6711
DOI
10.1016/j.stemcr.2021.09.013
language
English
LU publication?
yes
id
c9dd9a7f-6064-4665-b227-6ce4db71a793
date added to LUP
2022-04-05 15:17:30
date last changed
2022-10-02 23:03:28
@article{c9dd9a7f-6064-4665-b227-6ce4db71a793,
  abstract     = {{<p>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.</p>}},
  author       = {{Chandrasekaran, Abinaya and Dittlau, Katarina Stoklund and Corsi, Giulia I. and Haukedal, Henriette and Doncheva, Nadezhda T. and Ramakrishna, Sarayu and Ambardar, Sheetal and Salcedo, Claudia and Schmidt, Sissel I. and Zhang, Yu and Cirera, Susanna and Pihl, Maria and Schmid, Benjamin and Nielsen, Troels Tolstrup and Nielsen, Jørgen E. and Kolko, Miriam and Kobolák, Julianna and Dinnyés, András and Hyttel, Poul and Palakodeti, Dasaradhi and Gorodkin, Jan and Muddashetty, Ravi S. and Meyer, Morten and Aldana, Blanca I. and Freude, Kristine K.}},
  issn         = {{2213-6711}},
  keywords     = {{autophagy; CHMP2B; complement 3; cytokines; FTD3; hiPSC-derived astrocytes; mitochondria; NF-kB; reactive astrocytes}},
  language     = {{eng}},
  pages        = {{2736--2751}},
  publisher    = {{Cell Press}},
  series       = {{Stem Cell Reports}},
  title        = {{Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3}},
  url          = {{http://dx.doi.org/10.1016/j.stemcr.2021.09.013}},
  doi          = {{10.1016/j.stemcr.2021.09.013}},
  year         = {{2021}},
}