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Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington’s disease

ABSTRACT: Transcriptional dysregulation in Huntington’s disease (HD) causes functional deficits in striatal neurons. Here, we performed Patch-seq in an in vitro HD model to investigate the effects of mutant huntingtin (Htt) on synaptic transmission and gene transcription in single striatal neurons. We found that expression of mutant Htt decreased the synaptic output of striatal neurons in a cell autonomous fashion and identified a number of genes, whose dysregulation was correlated with physiological deficiencies in mutant Htt neurons. In support of a pivotal role for epigenetic mechanisms in HD pathophysiology, we found that inhibiting histone deacetylase 1/3 activities rectified several functional and morphological deficits and alleviated the aberrant transcriptional profiles in mutant Htt neurons. With this study, we demonstrate that Patch-seq technology can be applied both to better understand molecular mechanisms underlying a complex neurological disease at single-cell level and to provide a platform for screening for therapeutics for the disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE171099 | GEO | 2021/05/05

REPOSITORIES: GEO

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In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons

Project description:Huntington’s disease (HD), caused by a CAG repeat expansion in the huntingtin (HTT) gene, is characterized by abnormal protein aggregates and motor and cognitive dysfunction. Htt protein is ubiquitously expressed, but the striatal medium spiny neuron (MSN) is most susceptible to neuronal dysfunction and death. Abnormal gene expression represents a core pathogenic feature of HD, but the relative roles of cell-autonomous and non-cell-autonomous effects on transcription remain unclear. To determine the extent of cell-autonomous dysregulation in the striatum in vivo, we examined genome-wide RNA expression in symptomatic D9-N171-98Q (a.k.a. DE5) transgenic mice in which the forebrain expression of the first 171 amino acids of human Htt with a 98Q repeat expansion is limited to MSNs. Microarray data generated from these mice were compared to those generated on the identical array platform from a pan-neuronal HD mouse model, R6/2, carrying two different CAG repeat lengths, and a relatively high degree of overlap of changes in gene expression was revealed. We further focused on known canonical pathways associated with excitotoxicity, oxidative stress, mitochondrial dysfunction, dopamine signaling and trophic support, among others. While genes related to excitotoxicity, dopamine signaling and trophic support, were altered in both DE5 and R6/2 transgenic mice, which may be either cell-autonomous or non-cell-autonomous,, genes related to mitochondrial dysfunction, oxidative stress and the peroxisome proliferator-activated receptor are primarily affected in DE5 transgenic mice, indicating cell autonomous mechanisms Overall, our results demonstrate that HD-induced dysregulation of the striatal transcriptome can be largely attributed to intrinsic effects of mutant Htt,,such that mutant Htt-induced effects in cortical neurons is not necessary for striatal dysfunction/degeneration. Striatum from DE5 transgenic mice vs. wt littermate controls

2011-01-01 | E-GEOD-25232 | biostudies-arrayexpress

G3BP1-dependent suppression of polyglutamine aggregation in Huntington’s models and its failure upon stress granule formation

Project description:To define the interactome of huntingtin protein (HTT) in human neurons, we assessed interactors of HTT with coimmunoprecipitation experiments with huntingtin antibody or polyqlutamine antibody (it only recognizes mutant huntingtin protein with abnormal polyqlutamine expansion) in striatal neurons differentiated from control and patient-derived iPSC lines (HD-iPSCs). GFP antibody used as a negative control.

2022-12-02 | PXD037618 | Pride

RNA-Targeting CRISPR/Cas13d System Alleviates Disease-Related Phenotypes in Pre-clinical Models of Huntington’s Disease (Human).

Project description:Huntington's disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Although the pathogenesis of HD remains complex, the CAG-expanded (CAGEX) HTT mRNA and protein ultimately causes disease through a toxic gain-of-function mechanism. As the reduction of pathogenic mutant HTT mRNA is beneficial as a treatment, we developed a mutant allele-sensitive CAGEX RNA-targeting CRISPR-Cas13d system (Cas13d/CAGEX) that eliminates toxic CAGEX RNA in HD patient-derived fibroblasts and iPSC-derived striatal neurons. We show that intrastriatal delivery of Cas13d/CAGEX via a single adeno-associated viral vector, serotype 9 (AAV9) mediates significant and selective reduction of mutant HTT mRNA and protein levels within the striatum of heterozygous zQ175 mice, an established mouse model of HD. Moreover, the reduction of mutant HTT mRNA renders a sustained partial reversal of HD phenotypes, including improved motor coordination, attenuated striatal atrophy, and reduction of mutant HTT protein aggregates. Importantly, phenotypic improvements were durable for at least 8 months without gross or behavioral adverse effects, and with minimal off-target interactions of Cas13d/CAGEX in the mouse transcriptome. Taken together, we demonstrate a proof-of-principle of an RNA-targeting CRISPR/Cas13d system as a therapeutic approach for HD, a strategy with broad implications for the treatment of other dominantly inherited neurodegenerative disorders.

2022-11-15 | GSE214108 | GEO

RNA-Targeting CRISPR/Cas13d System Alleviates Disease-Related Phenotypes in Pre-clinical Models of Huntington’s Disease (Mouse).

2022-11-15 | GSE214109 | GEO

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.

2024-05-22 | GSE228254 | GEO

In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons

2011-01-01 | GSE25232 | 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

Experimental replacement therapy counters decreased IGF-1 levels in Huntington’s disease

Project description:Huntington’s disease (HD) is a monogenetic neurodegenerative disorder caused by the expansion of a polyglutamine (polyQ) stretch in huntingtin (htt). Here we show that mutant htt reduces the transcription of insulin-like growth factor 1 (IGF-1) and leads to loss of IGF-1 in HD brains, HD mouse models and mutant htt-transgenic microglial cells. IGF-1 replacement therapy by transplantation of genetically engineered mouse neuronal precursor cells (mNPCs) in a mouse model of HD reverted the motor phenotype and countered striatal neuronal loss.

2018-10-01 | GSE19291 | GEO

Truncation of mutant huntingtin in knock-in mice via CRISPR-Cas9 uncovers exon1 huntingtin as a key pathogenic form

Project description:It remains unknown how polyglutamine expansion in widely expressed proteins can cause selective neurodegeneration. In Huntington’s disease (HD), proteolytic processing generates toxic N-terminal huntingtin (HTT) fragments that preferentially kill striatal neurons. Considerable efforts have been devoted to investigating how HTT is cleaved and whether blocking its cleavage is therapeutically beneficial. However, using CRISPR-Cas9 to truncate full-length mutant Htt in HD140Q knock-in (KI) mice, we found that exon1 Htt is stably present in the brain, regardless of truncation sites in full-length Htt. This N-terminal Htt led to similar HD phenotypes and age-dependent Htt accumulation in striatum in different KI mice. Exon1 Htt is constantly generated but its selective accumulation in the striatum is caused by the age-dependent expression of striatum-enriched HspBP1, a chaperone inhibitory protein. Our findings suggest that tissue-specific chaperone function accounts for the selective neuropathology in HD and highlight therapeutic importance in regulating this function.

2020-04-21 | GSE145879 | GEO

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

Project description:Progressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntington’s disease (HD), but direct relationships between the huntingtin (HTT) protein and chromatin remain poorly described. Here, using chromatin immunoprecipitation and sequencing (ChIP-seq), we show that HTT reproducibly occupies specific locations in the mouse genome, including thousands of genomic loci that are differentially occupied in striatal tissue from a knock-in mouse model of the HD mutation (B6.HttQ111/+) versus wildtype controls. ChIP-seq of histone modifications, generated in parallel, revealed genotype-specific colocalization of HTT with trimethylation of histone 3 lysine 27 (H3K27me3), a repressive chromatin mark. Near genes that are differentially regulated in HD, greater HTT occupancy in HttQ111/+ vs. wildtype mice predicted increased H3K27me3, reduced histone 3 lysine 4 (H3K4me3), a marker of poised and active promoters, and down-regulated gene expression. Altered huntingtin-chromatin interactions may therefore play a direct role in driving transcriptional dysregulation in HD.

2023-05-16 | GSE150748 | GEO

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