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 Palakodeti; Jan Gorodkin; Ravi S Muddashetty; Morten Meyer; Blanca I Aldana; Kristine K Freude

doi:10.1016/j.stemcr.2021.09.013

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

24 Citations (Scopus)

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 language	English
Journal	Stem cell reports
Volume	16
Issue number	11
Pages (from-to)	2736-2751
Number of pages	16
ISSN	2213-6711
DOIs	https://doi.org/10.1016/j.stemcr.2021.09.013
Publication status	Published - 9 Nov 2021

Keywords

autophagy
CHMP2B
complement 3
cytokines
FTD3
hiPSC-derived astrocytes
mitochondria
NF-kB
reactive astrocytes

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Chandrasekaran, A., Dittlau, K. S., Corsi, G. I., Haukedal, H., Doncheva, N. T., Ramakrishna, S., Ambardar, S., Salcedo, C., Schmidt, S. I., Zhang, Y., Cirera, S., Pihl, M., Schmid, B., Nielsen, T. T., Nielsen, J. E., Kolko, M., Kobolák, J., Dinnyés, A., Hyttel, P., ... Freude, K. K. (2021). Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3. Stem cell reports, 16(11), 2736-2751. https://doi.org/10.1016/j.stemcr.2021.09.013

Chandrasekaran, A, Dittlau, KS, Corsi, GI, Haukedal, H, Doncheva, NT, Ramakrishna, S, Ambardar, S, Salcedo, C, Schmidt, SI, Zhang, Y, Cirera, S, Pihl, M, Schmid, B, Nielsen, TT , Nielsen, JE , Kolko, M, Kobolák, J, Dinnyés, A, Hyttel, P, Palakodeti, D, Gorodkin, J, Muddashetty, RS, Meyer, M, Aldana, BI & Freude, KK 2021, 'Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3', Stem cell reports, vol. 16, no. 11, pp. 2736-2751. https://doi.org/10.1016/j.stemcr.2021.09.013

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

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.",

keywords = "autophagy, CHMP2B, complement 3, cytokines, FTD3, hiPSC-derived astrocytes, mitochondria, NF-kB, reactive astrocytes",

author = "Abinaya Chandrasekaran and Dittlau, {Katarina Stoklund} and Corsi, {Giulia I} and Henriette Haukedal and Doncheva, {Nadezhda T} and Sarayu Ramakrishna and Sheetal Ambardar and Claudia Salcedo and Schmidt, {Sissel I} and Yu Zhang and Susanna Cirera and Maria Pihl and Benjamin Schmid and Nielsen, {Troels Tolstrup} and Nielsen, {J{\o}rgen E} and Miriam Kolko and Julianna Kobol{\'a}k and Andr{\'a}s Dinny{\'e}s and Poul Hyttel and Dasaradhi Palakodeti and Jan Gorodkin and Muddashetty, {Ravi S} and Morten Meyer and Aldana, {Blanca I} and Freude, {Kristine K}",

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AU - Chandrasekaran, Abinaya

AU - Dittlau, Katarina Stoklund

AU - Corsi, Giulia I

AU - Haukedal, Henriette

AU - Doncheva, Nadezhda T

AU - Ramakrishna, Sarayu

AU - Ambardar, Sheetal

AU - Salcedo, Claudia

AU - Schmidt, Sissel I

AU - Zhang, Yu

AU - Cirera, Susanna

AU - Pihl, Maria

AU - Schmid, Benjamin

AU - Nielsen, Troels Tolstrup

AU - Nielsen, Jørgen E

AU - Kolko, Miriam

AU - Kobolák, Julianna

AU - Dinnyés, András

AU - Hyttel, Poul

AU - Palakodeti, Dasaradhi

AU - Gorodkin, Jan

AU - Muddashetty, Ravi S

AU - Meyer, Morten

AU - Aldana, Blanca I

AU - Freude, Kristine K

PY - 2021/11/9

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AB - 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.

KW - autophagy

KW - CHMP2B

KW - complement 3

KW - cytokines

KW - FTD3

KW - hiPSC-derived astrocytes

KW - mitochondria

KW - NF-kB

KW - reactive astrocytes

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JO - Stem cell reports

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ER -

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

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