Astrocyte molecular signatures during Huntington’s disease progression and following huntingtin lowering with zinc finger protein transcriptional repressors
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ABSTRACT:
PROVIDER: PRJNA513983 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8423090_1.fastq.gz | Fastqsanger.gz | |||
| SRR8423090_2.fastq.gz | Fastqsanger.gz | |||
| SRR8423100_1.fastq.gz | Fastqsanger.gz | |||
| SRR8423100_2.fastq.gz | Fastqsanger.gz | |||
| SRR8423110_1.fastq.gz | Fastqsanger.gz |
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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
Project description:The Khakh laboratory used gfaABC1D-RiboTag AAVs to purify and sequence astrocyte actively translated mRNAs from Huntington's disease mouse models at several stages of the disease. Two weeks after AAV injection, striata were homogenized and RNA was purified from (i) cleared lysate as the input and control, and (ii) astrocyte-specific ribosome-associated RNA precipitated via a hemagglutinin (HA) tag. R6/2 mice are a fast developing model of Huntington's disease. Striatal cells show mutant HTT inclusions as early as 4 weeks of age. These mice show the first motor and cognitive symptoms around that age, but they become more evident around 8 week old and progressively impair until the mouse death that occurs around 13 weeks of age. Motor symptoms include increased paw clasping and grooming, impaired grip strength and rotarod performance, gait alterations, involuntary movements, etc. Cognitive impairment includes defects in learning and memory. NCAR mice are the healthy "non-carrier" controls for R6/2. They don't have unexpected phenotypes.
2020-01-08 | GSE124846 | GEO
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
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 | GSE162813 | GEO
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
Project description:Small molecule activation of a pseudoexon triggers huntingtin-lowering
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Project description:Huntington’s disease is caused by a polyglutamine repeat expansion at the N-terminus of the huntingtin protein which affects the function and folding of the protein, and results in intracellular protein aggregates. Here, we examined whether this mutation leads to altered ubiquitination of huntingtin and other proteins in both soluble and insoluble fractions of brain lysates of the Q175 knock-in Huntington disease mouse model and the Q20 wild-type mouse model. Ubiquitination sites are detected by identification of Gly-Gly (diGly) remnant motifs that remain on modified lysine residues after digestion. We identified K6, K9, K132, K804 and K837 as endogenous ubiquitination sites of soluble huntingtin, with wild-type huntingtin being mainly ubiquitinated at K132, K804 and K837. Mutant huntingtin protein levels were strongly reduced in the soluble fraction while K6 and K9 were mainly ubiquitinated. In the insoluble fraction increased levels of huntingtin K6 and K9 diGly sites were observed for mutant huntingtin as compared to wild type. Besides huntingtin, proteins with various roles, including membrane organization, transport, mRNA processing, gene transcription, translation, catabolic processes and oxidative phosphorylation, were differently expressed or ubiquitinated in wild-type and mutant huntingtin brain tissues. Correlating protein and diGly site fold-changes in the soluble fraction revealed that diGly site abundances of the majority of the proteins were not related to protein fold-changes, indicating that these proteins were differentially ubiquitinated in the Q175 mice. In contrast, both the fold-change of the protein level and diGly site level were increased for several proteins in the insoluble fraction, including ubiquitin, ubiquilin-2, sequestosome-1/p62 and myo5a. Our data sheds light on putative novel proteins involved in different cellular processes as well as their ubiquitination status in Huntington’s disease, which forms the basis for further mechanistic studies to understand the role of differential ubiquitination of huntingtin as well as ubiquitin-regulated processes in Huntington’s disease.
2019-06-05 | PXD010161 | Pride
Project description:Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease whose predominant neuropathological signature is the selective loss of medium spiny neurons in the striatum. Despite this selective neuropathology, the mutant protein (huntingtin) is found in virtually every cell so far studied, and, consequently, phenotypes are observed in a wide range of organ systems both inside and outside the central nervous system. We, and others, have suggested that peripheral dysfunction could contribute to the rate of progression of striatal phenotypes of HD. To test this hypothesis, we lowered levels of huntingtin by treating mice with antisense oligonucleotides (ASOs) targeting the murine Huntingtin gene. To study the relationship between peripheral huntingtin levels and striatal HD phenotypes, we utilized a knock-in model of the human HD mutation (the B6.HttQ111/+ mouse). We treated mice with ASOs from 2-10 months of age, a time period over which significant HD-relevant signs progressively develop in the brains of HttQ111/+ mice. Peripheral treatment with ASOs led to persistent reduction of huntingtin protein in peripheral organs, including liver (64% knockdown), brown adipose (66% knockdown), and white adipose tissues (71% knockdown). This reduction was not associated with alterations in the severity of HD-relevant signs in the striatum of HttQ111/+ mice at the end of the study, including transcriptional dysregulation, the accumulation of neuronal intranuclear inclusions, and behavioral changes such as subtle hypoactivity and reduced exploratory drive. These results suggest that the amount of peripheral reduction achieved in the current study does not significantly impact the progression of HD-relevant signs in the central nervous system.
2017-06-12 | GSE97101 | GEO