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Antisense oligonucleotide-mediated disruption of HTT caspase-6 cleavage site ameliorates the phenotype of YAC128 Huntington disease mice

ABSTRACT: Antisense oligonucleotide-mediated disruption of HTT caspase-6 cleavage site ameliorates the phenotype of YAC128 Huntington disease mice

PROVIDER: PRJNA998798 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25434200.fastq.gz	Fastqsanger.gz
	SRR25434201.fastq.gz	Fastqsanger.gz
	SRR25434202.fastq.gz	Fastqsanger.gz
	SRR25434171.fastq.gz	Fastqsanger.gz
	SRR25434172.fastq.gz	Fastqsanger.gz

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Antisense oligonucleotide-mediated disruption of HTT caspase-6 cleavage site ameliorates the phenotype of YAC128 Huntington disease mice

Project description:In Huntington’s Disease, cellular toxicity is particularly caused by toxic protein fragments generated from the mutant huntingtin (HTT) protein. By modifying the HTT protein, we aim to reduce proteolytic cleavage and ameliorate the consequences of mutant HTT without lowering total HTT levels. To that end, we use an antisense oligonucleotide (AON) that targets HTT pre-mRNA and induces partial skipping of exon 12, which contains the critical caspase-6 cleavage site. Here, we show that AON-treatment can partially restore the phenotype of YAC128 mice, a mouse model expressing the full-length human HTT gene including 128 CAG-repeats. Wild-type and YAC128 mice were treated intracerebroventricularly with AON12.1, scrambled AON or vehicle starting at 6 months of age and followed up to 12 months of age, when MRI was performed and mice were sacrificed. AON12.1 treatment induced around 40% exon skip and protein modification. The phenotype on body weight and activity, but not rotarod, was restored by AON treatment. Genes differentially expressed in YAC128 striatum changed towards wild-type levels and striatal volume was preserved upon AON12.1 treatment. However, scrambled AON also showed a restorative effect on gene expression and appeared to generally increase brain volume.

2023-12-01 | GSE239312 | GEO

Htt-N171 HD in vitro

Project description:4 Treatment groups: A) Uninfected B) Infected 6 weeks prior with GFP-expressing recombinant lentivirus C) Infected 6 weeks prior with Htt-N171-19Q-expressing recombinant lentivirus D)Infected 6 weeks prior with Htt-N171-82Q-expressing recombinant lentivirus Keywords = huntington Keywords: parallel sample

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Proteolysis resistant huntingtin isoform induced by antisense oligonucleotide maintains normal huntingtin function in mouse

Project description:Huntington’s disease (HD) is a late onset neurological disorder for which no neuroprotective therapies efficiently delay onset or progression. A key pathological mechanism in disease involves the proteolysis of polyglutamine (polyQ)-expanded mutant huntingtin (mHTT) generating polyQ-containing N-terminal fragments that are crucial contributors to HD pathogenesis since inhibition of the cleavage at the putative caspase-6 site reduces pathology in a HD mouse model. Interestingly, a naturally occurring alternative spliced form of HTT lacking exon12 (HTTΔ12) leads to a protein with an internal deletion of the caspase-6 N-terminal cleavage site. Here, we have taken a multidisciplinary approach to characterize the therapeutic potential of targeting exon12 of HTT. We show that HTTΔ12 is fully resistant to caspase-6 cleavage in both cell-free and tissue lysate assays, while maintaining overall biochemical and structural properties similar to wild-type (wt)-HTT. We generated mouse deleted for exon12 and found that exon12 is dispensable for HTT main physiological functions including embryonic development and intracellular trafficking such as BDNF transport. Finally, we pharmacologically induced HTTΔ12 using an antisense oligonucleotide (ASO). QRX-704 ASO efficiently distributes in the whole brain, is stable several months, and reduces pathogenic proteolysis. Thus, ASO-induced exon12 deletion of HT We performed gene expression profiling analysis using data obtained from RNA-seq of brain tissue (cortex and striatum) samples originating from mouse littermates from HttΔ12 (Δ12;KI) and HttKO (KO) lines at 3 month of age.

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Project description:Data from Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo CoIP of HTT full length and fragment proteins from mouse cortical lysates. Controlled with preimmune mouse IgG IP.

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Antisense oligonucleotide therapy for calmodulinopathy

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Mono and biallelic inactivation of Huntingtin gene in patient-specific iPS cells reveal HTT roles in striatal development and in neuronal functions impaired in Huntington’s disease

Project description:Mutations in the Huntingtin (HTT) gene cause Huntington disease (HD), a neurodegenerative disorder. While HTT is known to be involved, as a scaffold protein, in several cellular functions, its normal and pathogenic functions during the development of the human forebrain remain poorly understood. To investigate the roles of wild-type and mutant HTT alleles during human neural and striatal development we inactivated HTT alleles in a series of isogenic clones of a human induced pluripotent stem cell (iPSC) line derived from a patient with HD. We show that the loss of wild-type, mutant, or both HTT isoforms did not affect the pluripotency of iPSCs or their transition into neural cells. However, we observed that HTT loss caused division impairments in forebrain neuro-epithelial cells. Moreover, HTT-/- derivatives displayed impaired maturation of medium spiny neurons (MSNs) particularly in the acquisition of DARPP32 expression, a key functional marker of MSNs. Finally, we discovered that MSNs and cortical neurons derived from HTT-/- clones exhibited higher levels of baseline DNA damage and lower BDNF axonal transport, two cellular dysfunctions previously described in HD neurons.

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Expression data from human Huntington fibroblasts

2013-03-28 | GSE45516 | GEO

Expression data from human Huntington fibroblasts

Project description:Gene expression profile comparison from fibroblasts of Huntington individuals and normal ones We used microarrays to detail the global gene expression of fibroblasts from Huntington patients Comparison between six Huntington human fibroblasts and three normal controls. All individuals were aged and sex matched. In fact they are all males with the subsequent ages: 28, 48, 57 for the controls and 38, 63, 57, 47, 38, 37 for the HD patients. The average age is comparable.

2013-03-28 | E-GEOD-45516 | biostudies-arrayexpress

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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ChIP-seq of HTT protein in mouse cortex following HTT knockdown

Project description:ChIP-seq of HTT protein in mouse cortex following HTT knockdown

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