Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure

Pawel Lisowski; Selene Lickfett; Agnieszka Rybak-Wolf; Carmen Menacho; Stephanie Le; Tancredi Massimo Pentimalli; Sofia Notopoulou; Werner Dykstra; Daniel Oehler; Sandra López-Calcerrada; Barbara Mlody; Maximilian Otto; Haijia Wu; Yasmin Richter; Philipp Roth; Ruchika Anand; Linda A M Kulka; David Meierhofer; Petar Glazar; Ivano Legnini; Narasimha Swamy Telugu; Tobias Hahn; Nancy Neuendorf; Duncan C Miller; Annett Böddrich; Amin Polzin; Ertan Mayatepek; Sebastian Diecke; Heidi Olzscha; Janine Kirstein; Cristina Ugalde; Spyros Petrakis; Sidney Cambridge; Nikolaus Rajewsky; Ralf Kühn; Erich E Wanker; Josef Priller; Jakob J Metzger; Alessandro Prigione

doi:10.1038/s41467-024-51216-w

Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure

Pawel Lisowski, Selene Lickfett, Agnieszka Rybak-Wolf, Carmen Menacho, Stephanie Le, Tancredi Massimo Pentimalli, Sofia Notopoulou, Werner Dykstra, Daniel Oehler, Sandra López-Calcerrada, Barbara Mlody, Maximilian Otto, Haijia Wu, Yasmin Richter, Philipp Roth, Ruchika Anand, Linda A M Kulka, David Meierhofer, Petar Glazar, Ivano LegniniNarasimha Swamy Telugu, Tobias Hahn, Nancy Neuendorf, Duncan C Miller, Annett Böddrich, Amin Polzin, Ertan Mayatepek, Sebastian Diecke, Heidi Olzscha, Janine Kirstein, Cristina Ugalde, Spyros Petrakis, Sidney Cambridge, Nikolaus Rajewsky, Ralf Kühn, Erich E Wanker, Josef Priller, Jakob J Metzger^*, Alessandro Prigione^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT) causes the neurodegenerative disorder Huntington's disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered male induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. The introduction of a 70Q mutation caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics that was reverted upon overexpression of CHCHD2. Removing the poly-Q tract from HTT normalized CHCHD2 levels and corrected key mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early interventional target for HD.

Original language	English
Pages (from-to)	7027
Journal	Nature Communications
Volume	15
Issue number	1
Early online date	22 Aug 2024
DOIs	https://doi.org/10.1038/s41467-024-51216-w
Publication status	E-pub ahead of print - 22 Aug 2024

Keywords / Materials (for Non-textual outputs)

Humans
Transcription Factors/metabolism
DNA-Binding Proteins/metabolism
Huntingtin Protein/genetics
Organoids/metabolism
Mitochondrial Proteins/metabolism
Brain/metabolism
Huntington Disease/metabolism
Induced Pluripotent Stem Cells/metabolism
Male
Mitochondria/metabolism
Mutation
Mitochondrial Dynamics/genetics

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10.1038/s41467-024-51216-w

s41467-024-51216-wFinal published version, 9.07 MBLicence: Creative Commons: Attribution (CC-BY)

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Lisowski, P., Lickfett, S., Rybak-Wolf, A., Menacho, C., Le, S., Pentimalli, T. M., Notopoulou, S., Dykstra, W., Oehler, D., López-Calcerrada, S., Mlody, B., Otto, M., Wu, H., Richter, Y., Roth, P., Anand, R., Kulka, L. A. M., Meierhofer, D., Glazar, P., ... Prigione, A. (2024). Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure. Nature Communications, 15(1), 7027. Advance online publication. https://doi.org/10.1038/s41467-024-51216-w

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title = "Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure",

abstract = "Expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT) causes the neurodegenerative disorder Huntington's disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered male induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. The introduction of a 70Q mutation caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics that was reverted upon overexpression of CHCHD2. Removing the poly-Q tract from HTT normalized CHCHD2 levels and corrected key mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early interventional target for HD.",

keywords = "Humans, Transcription Factors/metabolism, DNA-Binding Proteins/metabolism, Huntingtin Protein/genetics, Organoids/metabolism, Mitochondrial Proteins/metabolism, Brain/metabolism, Huntington Disease/metabolism, Induced Pluripotent Stem Cells/metabolism, Male, Mitochondria/metabolism, Mutation, Mitochondrial Dynamics/genetics",

author = "Pawel Lisowski and Selene Lickfett and Agnieszka Rybak-Wolf and Carmen Menacho and Stephanie Le and Pentimalli, {Tancredi Massimo} and Sofia Notopoulou and Werner Dykstra and Daniel Oehler and Sandra L{\'o}pez-Calcerrada and Barbara Mlody and Maximilian Otto and Haijia Wu and Yasmin Richter and Philipp Roth and Ruchika Anand and Kulka, {Linda A M} and David Meierhofer and Petar Glazar and Ivano Legnini and Telugu, {Narasimha Swamy} and Tobias Hahn and Nancy Neuendorf and Miller, {Duncan C} and Annett B{\"o}ddrich and Amin Polzin and Ertan Mayatepek and Sebastian Diecke and Heidi Olzscha and Janine Kirstein and Cristina Ugalde and Spyros Petrakis and Sidney Cambridge and Nikolaus Rajewsky and Ralf K{\"u}hn and Wanker, {Erich E} and Josef Priller and Metzger, {Jakob J} and Alessandro Prigione",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = aug,

day = "22",

doi = "10.1038/s41467-024-51216-w",

language = "English",

volume = "15",

pages = "7027",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Lisowski, P, Lickfett, S, Rybak-Wolf, A, Menacho, C, Le, S, Pentimalli, TM, Notopoulou, S, Dykstra, W, Oehler, D, López-Calcerrada, S, Mlody, B, Otto, M, Wu, H, Richter, Y, Roth, P, Anand, R, Kulka, LAM, Meierhofer, D, Glazar, P, Legnini, I, Telugu, NS, Hahn, T, Neuendorf, N, Miller, DC, Böddrich, A, Polzin, A, Mayatepek, E, Diecke, S, Olzscha, H, Kirstein, J, Ugalde, C, Petrakis, S, Cambridge, S, Rajewsky, N, Kühn, R, Wanker, EE, Priller, J, Metzger, JJ & Prigione, A 2024, 'Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure', Nature Communications, vol. 15, no. 1, pp. 7027. https://doi.org/10.1038/s41467-024-51216-w

TY - JOUR

T1 - Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure

AU - Lisowski, Pawel

AU - Lickfett, Selene

AU - Rybak-Wolf, Agnieszka

AU - Menacho, Carmen

AU - Le, Stephanie

AU - Pentimalli, Tancredi Massimo

AU - Notopoulou, Sofia

AU - Dykstra, Werner

AU - Oehler, Daniel

AU - López-Calcerrada, Sandra

AU - Mlody, Barbara

AU - Otto, Maximilian

AU - Wu, Haijia

AU - Richter, Yasmin

AU - Roth, Philipp

AU - Anand, Ruchika

AU - Kulka, Linda A M

AU - Meierhofer, David

AU - Glazar, Petar

AU - Legnini, Ivano

AU - Telugu, Narasimha Swamy

AU - Hahn, Tobias

AU - Neuendorf, Nancy

AU - Miller, Duncan C

AU - Böddrich, Annett

AU - Polzin, Amin

AU - Mayatepek, Ertan

AU - Diecke, Sebastian

AU - Olzscha, Heidi

AU - Kirstein, Janine

AU - Ugalde, Cristina

AU - Petrakis, Spyros

AU - Cambridge, Sidney

AU - Rajewsky, Nikolaus

AU - Kühn, Ralf

AU - Wanker, Erich E

AU - Priller, Josef

AU - Metzger, Jakob J

AU - Prigione, Alessandro

PY - 2024/8/22

Y1 - 2024/8/22

N2 - Expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT) causes the neurodegenerative disorder Huntington's disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered male induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. The introduction of a 70Q mutation caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics that was reverted upon overexpression of CHCHD2. Removing the poly-Q tract from HTT normalized CHCHD2 levels and corrected key mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early interventional target for HD.

AB - Expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT) causes the neurodegenerative disorder Huntington's disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered male induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. The introduction of a 70Q mutation caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics that was reverted upon overexpression of CHCHD2. Removing the poly-Q tract from HTT normalized CHCHD2 levels and corrected key mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early interventional target for HD.

KW - Humans

KW - Transcription Factors/metabolism

KW - DNA-Binding Proteins/metabolism

KW - Huntingtin Protein/genetics

KW - Organoids/metabolism

KW - Mitochondrial Proteins/metabolism

KW - Brain/metabolism

KW - Huntington Disease/metabolism

KW - Induced Pluripotent Stem Cells/metabolism

KW - Male

KW - Mitochondria/metabolism

KW - Mutation

KW - Mitochondrial Dynamics/genetics

U2 - 10.1038/s41467-024-51216-w

DO - 10.1038/s41467-024-51216-w

M3 - Article

C2 - 39174523

SN - 2041-1723

VL - 15

SP - 7027

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure

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Keywords / Materials (for Non-textual outputs)

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