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Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure [organoids]

ABSTRACT: Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure [organoids]

PROVIDER: PRJNA978533 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24795226_1.fastq.gz	Fastqsanger.gz
	SRR24795226_2.fastq.gz	Fastqsanger.gz
	SRR24795227_1.fastq.gz	Fastqsanger.gz
	SRR24795227_2.fastq.gz	Fastqsanger.gz
	SRR24795228_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure [organoids]

Project description: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 induced pluripotent stem cells to introduce a 70Q expansion or remove the poly-Q tract of HTT. 70Q introduction 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), which is involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics and elevated resting energy expenditure. Elimination of the poly-Q tract of HTT normalized CHCHD2 expression and 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 intervention target for HD.

2024-07-23 | GSE233895 | GEO

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

Project description:Expansion of the poly-glutamine (Q) tract 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 induced pluripotent stem cells to introduce a 70Q expansion or remove the poly-Q tract. mHTT introduction caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), which is involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics and elevated resting energy expenditure. Elimination of the poly-Q tract reverted CHCHD2 expression and mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then represent a target of early intervention for HD.

2024-06-21 | PXD041846 | Pride

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

Project description: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 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 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.

2024-07-23 | GSE271852 | GEO

Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure [NGN2]

2024-07-23 | GSE233914 | GEO

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

Project description:Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure

| PRJNA978559 | ENA

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

Project description:Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure

| PRJNA1137078 | ENA

Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure [NGN2]

Project description:Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure [NGN2]

| PRJNA978567 | ENA

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

Project description: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.

| S-EPMC11341898 | biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-07-23 | GSE233916 | GEO

Regionally defined proteomic profiles of human cerebral tissue and organoids reveal conserved molecular modules of neurodevelopment

Project description:Cerebral organoids have emerged as faithful humanoid avatars for modeling neurodevelopmental and pathological processes. Additionally, they serve as powerful discovery platforms for less characterized neurobiological programs. Towards this prospect, we leveraged mass spectrometry-based proteomics to molecularly profile precursor and neural compartments of both human-derived organoids and mid-gestation fetal brain tissue, to define overlapping programs. Our analysis included precursor-enriched transcriptional regulatory proteins that were not found to be differentially expressed in previous transcriptomic datasets. To highlight the discovery potential of this resource, we show that RUVBL2 is preferentially expressed in the SOX2-positive compartment of organoids and chemical inactivation leads to precursor cell displacement and apoptosis. To explore clinicopathological correlates of this cytoarchitectural disruption, we interrogated clinical datasets, and identified rare de novo genetic variants involving RUVBL2 in patients with neurodevelopmental impairments. Together, our study demonstrates how cell-type specific profiling of organoids can help nominate previously unappreciated genes in neurodevelopment and disease.

2022-04-07 | PXD033012 | Pride

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