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Neuronal and astrocytic contributions to Huntington’s disease dissected following mutant Huntingtin (mHTT) lowering

ABSTRACT: Neuronal and astrocytic contributions to Huntington’s disease dissected following mutant Huntingtin (mHTT) lowering

PROVIDER: PRJNA872520 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21228700_1.fastq.gz	Fastqsanger.gz
	SRR21228700_2.fastq.gz	Fastqsanger.gz
	SRR21228701_1.fastq.gz	Fastqsanger.gz
	SRR21228701_2.fastq.gz	Fastqsanger.gz
	SRR21228702_1.fastq.gz	Fastqsanger.gz

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Neuronal and astrocytic contributions to Huntington’s disease dissected following mutant Huntingtin (mHTT) lowering

Project description:We used cell-specific zinc finger protein (ZFP) transcriptional repressors to lower mHTT and experimentally evaluated the consequences of neuronal and astrocytic mHTT lowering on HD pathophysiology using cell-type specific RNA-seq

2022-12-15 | GSE211891 | GEO

Neuronal and astrocytic contributions to Huntington’s disease dissected following mutant Huntingtin (mHTT) lowering

Project description:Huntington’s disease (HD) is caused by expanded CAG repeats in the Huntingtin gene (HTT) that results in expression of mutant HTT proteins (mHTT) with extended polyglutamine tracts in diverse cells of the body, including striatal neurons and astrocytes. The relative contributions of neurons and astrocytes to disease pathogenesis are unknown for HD and other neurodegenerative diseases. This is a critical issue to address since it has been proposed that neuronal loss in HD and other major neurodegenerative diseases is downstream of astrocytic dysfunction that drives neuronal death. Moreover, astrocyte-to-neuron conversion is considered a promising approach in HD and other neurodegenerative diseases with little reported detriment with regards to normal astrocytic physiological functions, which are varied and extensive in health and disease. Thus, astrocytes are considered both causative and also largely replaceable in neurodegeneration, and their basic contributions to disease pathophysiology relative to neurons remain undefined in vivo. We used genetically encoded and cell-specific zinc finger protein (ZFP) transcriptional repressors to lower mHTT and molecularly dissected neuronal and astrocytic influences on HD pathophysiology at molecular, cellular, and behavioral levels. We found that the major disease drivers were in fact neurons, with astrocytes displaying lesser loss of essential functions such as cholesterol metabolism that were downstream of greater neuronal dysfunction, which encompassed neuromodulation, synaptic, and intracellular signaling. We thus dissected the cell autonomous and non-cell autonomous mechanistic and causal contributions of both neurons and astrocytes to a complex neurodegenerative disease in vivo with wider implications for rescue and repair strategies.

2022-12-15 | PXD030021 | Pride

Small molecule activation of a pseudoexon triggers huntingtin-lowering

Project description:Small molecule activation of a pseudoexon triggers huntingtin-lowering

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Small molecule activation of a pseudoexon triggers huntingtin-lowering (AmpliSeq)

Project description:Small molecule activation of a pseudoexon triggers huntingtin-lowering (AmpliSeq)

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Small molecule activation of a pseudoexon triggers huntingtin-lowering (AmpliSeq)

Project description:Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by abnormal expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene (HTT). The resultant mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin protein (HTT) levels alleviates HD-associated motor and neuropathological abnormalities, confirming the importance of huntingtin-lowering as a therapeutic approach. Several therapies in development repress HTT transcription or translation, including antisense oligonucleotides, virally-delivered microRNAs, and zinc finger protein transcription factors. However, they all require invasive procedures to reach the central nervous system (CNS) and do not distribute evenly to target areas in the brain. Systemically distributed therapeutics are needed to address the CNS and peripheral dysfunctions associated with HD. Here we report the discovery of small molecule splicing modifiers that lower HTT expression by selective modulation of pre-mRNA splicing. These compounds promote the inclusion of a pseudoexon containing a premature termination codon triggering HTT mRNA degradation and a reduction of HTT protein levels in vitro and in vivo. These orally bioavailable small molecules represent a non-invasive treatment option for HD and our findings support their continued development for the treatment of HD.

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Small molecule activation of a pseudoexon triggers huntingtin-lowering (RNA-Seq)

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Astrocyte-neuron contributions to Huntington’s disease dissected with ZFPs

Project description:Astrocyte-neuron contributions to Huntington’s disease dissected with ZFPs

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Small molecule activation of a pseudoexon triggers huntingtin-lowering (RNA-Seq)

Project description:Small molecule activation of a pseudoexon triggers huntingtin-lowering (RNA-Seq)

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Astrocyte molecular signatures during Huntington’s disease progression and following huntingtin lowering with zinc finger protein transcriptional repressors

Project description:Astrocyte molecular signatures during Huntington’s disease progression and following huntingtin lowering with zinc finger protein transcriptional repressors

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Astrocyte-neuron contributions to Huntington’s disease dissected with ZFPs

Project description:We performed cell-type specific RNAseq in astrocytes and neurons in the presence or absence of ZFP transcriptional repressors in the striatum of R6/2 mouse model of HD.

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