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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pluripotent Stem Cell

SUBMITTER: David Meierhofer

LAB HEAD: Alessandro Prigione

PROVIDER: PXD041846 | Pride | 2024-06-21

REPOSITORIES: Pride

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			Action	DRS
	180Q_patient_D1.raw	Raw
	180Q_patient_SCX_3.raw	Raw
	180Q_patient_SCX_4.raw	Raw
	180Q_patient_SCX_5.raw	Raw
	180Q_patient_SCX_X.raw	Raw

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

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.

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

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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.

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Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s Disease

Project description:Huntington’s disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type and mHTT are regulated by a stress-responsive upstream open reading frame, and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.

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Mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein

Project description:Ribosomes translocate one codon at a time in mRNA during protein synthesis, but the regulators of ribosome translocation and their impact on neurodegenerative disease remain poorly understood. Here, we show that huntingtin (Htt) and its poly-Q expanded form, mHtt, a cause of Huntington disease (HD), promotes ribosome stalling and suppresses protein synthesis in vivo and in vitro. We found that fragile mental retardation protein (FMRP), a known promoter of ribosome stalling, is upregulated in HD cells and patients’ tissue. Unexpectedly, FMRP depletion fails to reverse mHtt-mediated ribosome stalling in HD cells. mHtt binds directly to ribosomes in a RNase-sensitive manner and interacts with ribosomal proteins. Combining high-resolution ribosome footprint profiling (Ribo-Seq) and RNA-Seq, we provide a global snapshot of stalling on mRNA transcripts, with a shift in ribosome occupancy toward the 5’ and 3’ end and single-codon unique pauses in HD cells. We also found ribosomes that appear to have stalled in mHtt mRNA before CAG repeat expansion. Thus, Htt regulates protein synthesis via ribosome stalling mechanisms and in turn may affect mRNA elongation, which may be exploited for HD therapeutics.

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Expression data from Human Fetal Astrocytes and Neurons transduced with WT and mutant HTT

Project description:Glial pathology has been implicated as a causal contributor to the dysfunction and death of striatal neurons that characterizes Huntington disease. In this study, we investigated mutant HTT (mHTT)-associated changes in gene expression by both mouse and human striatal astrocytes. Mouse striatal astrocytes were FACS-sorted from two distinct models, R6/2 and zQ175 mice, which respectively express exon1-only truncated or full-length HTT, while human astrocytes were generated from either hESCs expressing full-length mHTT, or fetal striatal glia transduced with exon1-only mHTT. Comparison of differential gene expression between each of these conditions and their normal HTT controls, and to one another, revealed astrocyte-specific alterations in both truncated and full-length mHTT models that were shared by both species, yet with differences that clearly distinguished glia derived from each model. Overlap of these data sets revealed that the patterns of mHTT-associated transcriptional dysregulation depended not only upon species, but also upon whether the astroglia expressed truncated or full-length mHTT. These data revealed a common set of conserved, mHTT-associated dysregulated pathways that may present targets for the rescue of glial pathology in HD, while revealing that the gene expression of glia expressing truncated mHTT may differ substantially from that of glia expressing full-length mHTT.

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