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Small molecule activation of a pseudoexon triggers huntingtin-lowering

ABSTRACT: Small molecule activation of a pseudoexon triggers huntingtin-lowering

PROVIDER: PRJNA683073 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13209900.fastq.gz	Fastqsanger.gz
	SRR13209901.fastq.gz	Fastqsanger.gz
	SRR13209902_1.fastq.gz	Fastqsanger.gz
	SRR13209902_2.fastq.gz	Fastqsanger.gz
	SRR13209903_1.fastq.gz	Fastqsanger.gz

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

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

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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.

2021-07-01 | GSE162812 | GEO

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

2021-07-01 | GSE162813 | GEO

Small molecule activation of a pseudoexon triggers huntingtin-lowering

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

2021-07-01 | GSE162814 | GEO

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

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

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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

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

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Small molecule-induced polymerization triggers degradation of BCL6

Project description:Most small-molecule protein degraders act as interface stabilizers ‘molecular glues’ between E3 ubiquitin ligases and target proteins to induce ternary complex formation and ubiquitin-dependent target protein degradation. Here we report polymerization as a novel mechanism for small molecule-induced degradation. Using functional screens in combination with molecular and biochemical assays, we found that BI-3802, which binds to the BTB domain of the oncogenic transcription factor BCL6, induces polymerization of BCL6 into regular helical structures in vitro and foci in vivo. Polymerization precedes degradation by the SIAH1 E3 ubiquitin ligase. Hereby, a VxP amino acid motif on BCL6, distal from the drug-binding BTB domain, is required for SIAH1 binding, ubiquitination and BI-3802-induced degradation. Our findings propose that small molecule-induced polymerization is not only a new modality for targeted protein degradation, but also provides synthetic biology with a tool for tunable protein polymerization and opens new avenues for future drug design.

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Huntingtin Lowering Strategies.

Project description:Trials using antisense oligonucleotide technology to lower Huntingtin levels in Huntington's disease (HD) are currently ongoing. This progress, taking place only 27 years after the identification of the Huntingtin gene (HTT) in 1993 reflects the enormous development in genetic engineering in the last decades. It is also the result of passionate basic scientific work and large worldwide registry studies that have advanced the understanding of HD. Increased knowledge of the pathophysiology of this autosomal dominantly inherited CAG-repeat expansion mediated neurodegenerative disease has led to the development of several putative treatment strategies, currently under investigation. These strategies span the whole spectrum of potential targets from genome editing via RNA interference to promoting protein degradation. Yet, recent studies revealed the importance of huntingtin RNA in the pathogenesis of the disease. Therefore, huntingtin-lowering by means of RNA interference appears to be a particular promising strategy. As a matter of fact, these approaches have entered, or are on the verge of entering, the clinical trial period. Here, we provide an overview of huntingtin-lowering approaches via DNA or RNA interference in present clinical trials as well as strategies subject to upcoming therapeutic options. We furthermore discuss putative implications for future treatment of HD patients.

| S-EPMC7139361 | biostudies-literature

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