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Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction

Fatal familial insomnia (FFI) is a rare neurodegenerative disease caused by a dominantly inherited single amino acid substitution (D178N) within the prion protein (PrP). No in vitro human brain tissue model for this disease has previously been available. Consequently, how this mutation exerts its da...

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Autores principales: Foliaki, Simote T., Smith, Anna, Schwarz, Benjamin, Bohrnsen, Eric, Bosio, Catharine M., Williams, Katie, Orrú, Christina D., Lachenauer, Hailey, Groveman, Bradley R., Haigh, Cathryn L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9851538/
https://www.ncbi.nlm.nih.gov/pubmed/36656833
http://dx.doi.org/10.1371/journal.pgen.1010565
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author Foliaki, Simote T.
Smith, Anna
Schwarz, Benjamin
Bohrnsen, Eric
Bosio, Catharine M.
Williams, Katie
Orrú, Christina D.
Lachenauer, Hailey
Groveman, Bradley R.
Haigh, Cathryn L.
author_facet Foliaki, Simote T.
Smith, Anna
Schwarz, Benjamin
Bohrnsen, Eric
Bosio, Catharine M.
Williams, Katie
Orrú, Christina D.
Lachenauer, Hailey
Groveman, Bradley R.
Haigh, Cathryn L.
author_sort Foliaki, Simote T.
collection PubMed
description Fatal familial insomnia (FFI) is a rare neurodegenerative disease caused by a dominantly inherited single amino acid substitution (D178N) within the prion protein (PrP). No in vitro human brain tissue model for this disease has previously been available. Consequently, how this mutation exerts its damaging effect on brain cells is still unknown. Using CRISPR-Cas9 engineered induced pluripotent stem cells, we made D178N cerebral organoids and compared these with isotype control organoids. We found that, in the absence of other hallmarks of FFI, the D178N organoids exhibited astrogliosis with cellular oxidative stress. Abnormal post-translational processing of PrP was evident but no tissue deposition or propagation of mis-folded PrP isoforms were observed. Neuronal electrophysiological function was compromised and levels of neurotransmitters, particularly acetylcholine and GABA, altered. Underlying these dysfunctions were changes in cellular energy homeostasis, with substantially increased glycolytic and Krebs cycle intermediates, and greater mitochondrial activity. This increased energy demand in D178N organoids was associated with increased mitophagy and depletion of lipid droplets, in turn resulting in shifts of cellular lipid composition. Using a double mutation (178NN) we could confirm that most changes were caused by the presence of the mutation rather than interaction with PrP molecules lacking the mutation. Our data strongly suggests that shifting biosynthetic intermediates and oxidative stress, caused by an imbalance of energy supply and demand, results in astrogliosis with compromised neuronal activity in FFI organoids. They further support that many of the disease associated changes are due to a corruption of PrP function and do not require propagation of PrP mis-folding.
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spelling pubmed-98515382023-01-20 Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction Foliaki, Simote T. Smith, Anna Schwarz, Benjamin Bohrnsen, Eric Bosio, Catharine M. Williams, Katie Orrú, Christina D. Lachenauer, Hailey Groveman, Bradley R. Haigh, Cathryn L. PLoS Genet Research Article Fatal familial insomnia (FFI) is a rare neurodegenerative disease caused by a dominantly inherited single amino acid substitution (D178N) within the prion protein (PrP). No in vitro human brain tissue model for this disease has previously been available. Consequently, how this mutation exerts its damaging effect on brain cells is still unknown. Using CRISPR-Cas9 engineered induced pluripotent stem cells, we made D178N cerebral organoids and compared these with isotype control organoids. We found that, in the absence of other hallmarks of FFI, the D178N organoids exhibited astrogliosis with cellular oxidative stress. Abnormal post-translational processing of PrP was evident but no tissue deposition or propagation of mis-folded PrP isoforms were observed. Neuronal electrophysiological function was compromised and levels of neurotransmitters, particularly acetylcholine and GABA, altered. Underlying these dysfunctions were changes in cellular energy homeostasis, with substantially increased glycolytic and Krebs cycle intermediates, and greater mitochondrial activity. This increased energy demand in D178N organoids was associated with increased mitophagy and depletion of lipid droplets, in turn resulting in shifts of cellular lipid composition. Using a double mutation (178NN) we could confirm that most changes were caused by the presence of the mutation rather than interaction with PrP molecules lacking the mutation. Our data strongly suggests that shifting biosynthetic intermediates and oxidative stress, caused by an imbalance of energy supply and demand, results in astrogliosis with compromised neuronal activity in FFI organoids. They further support that many of the disease associated changes are due to a corruption of PrP function and do not require propagation of PrP mis-folding. Public Library of Science 2023-01-19 /pmc/articles/PMC9851538/ /pubmed/36656833 http://dx.doi.org/10.1371/journal.pgen.1010565 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Foliaki, Simote T.
Smith, Anna
Schwarz, Benjamin
Bohrnsen, Eric
Bosio, Catharine M.
Williams, Katie
Orrú, Christina D.
Lachenauer, Hailey
Groveman, Bradley R.
Haigh, Cathryn L.
Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction
title Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction
title_full Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction
title_fullStr Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction
title_full_unstemmed Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction
title_short Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction
title_sort altered energy metabolism in fatal familial insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9851538/
https://www.ncbi.nlm.nih.gov/pubmed/36656833
http://dx.doi.org/10.1371/journal.pgen.1010565
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