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Project description:Aberrant neuronal development and the persistence of mitotic cellular populations have been implicated in a multitude of neurological disorders, including Huntington's disease (HD). However, the mechanism underlying this potential pathology remains unclear. We used a modified protocol to differentiate induced pluripotent stem cells (iPSCs) from HD patients and unaffected controls into neuronal cultures enriched for medium spiny neurons, the cell type most affected in HD. We performed single-cell and bulk transcriptomic and epigenomic analyses and demonstrated that a persistent cyclin D1+ neural stem cell (NSC) population is observed selectively in adult-onset HD iPSCs during differentiation. Treatment with a WNT inhibitor abrogates this NSC population while preserving neurons. Taken together, our findings identify a mechanism that may promote aberrant neurodevelopment and adult neurogenesis in adult-onset HD striatal neurons with the potential for therapeutic compensation.
| S-EPMC7066322 | biostudies-literature
Project description:Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation
| PRJNA610449 | ENA
Project description: Not available
| S-EPMC8762510 | biostudies-literature
Project description:BackgroundHuntington's disease (HD) is an inherited neurodegenerative disease and is characterized by atrophy of certain regions of the brain in a progressive manner. HD patients experience behavioral changes and uncontrolled movements which can be primarily attributed to the atrophy of striatal neurons. Previous publications describe the models of the HD striatum using induced pluripotent stem cells (iPSCs) derived from HD patients with a juvenile onset (JHD). In this model, the JHD iPSC-derived striatal cultures had altered neurodevelopment and contained a high number of nestin expressing progenitor cells at 42 days of differentiation.ObjectiveTo further characterize the altered neurodevelopmental phenotype and evaluate potential phenotypic reversal.MethodsDifferentiation of human iPSCs towards striatal fate and characterization by means of immunocytochemistry and stereological quantification.ResultsHere this study demonstrates a distinct delay in the differentiation of the JHD neural progenitor population. However, reduction of the JHD aberrant progenitor populations can be accomplished either by targeting the canonical Notch signaling pathway or by treatment with HTT antisense oligonucleotides (ASOs).ConclusionsIn summary, this data is postulated to reflect a potential overall developmental delay in JHD.
| S-EPMC6839479 | biostudies-literature
Project description:Neuronal ceroid lipofuscinosis (NCL) is composed of a group of inherited neurodegenerative diseases, with the hallmark of lipofuscin deposit (a mixture of lipids and proteins with metal materials) inside the lysosomal lumen, which typically emits auto-fluorescence. Adult-onset NCL (ANCL) has been reported to be associated with a mutation in the DNAJC5 gene, including L115R, L116Δ, and the recently identified C124_C133dup mutation. In this study, we reported a novel C128Y mutation in a young Chinese female with ANCL, and this novel mutation caused abnormal palmitoylation and triggered lipofuscin deposits.
| S-EPMC9031920 | biostudies-literature
Project description:BackgroundIn this study, we asked whether differences in striatal activity during a reinforcement learning (RL) task with gain and loss domains could be one of the earliest functional imaging features associated with carrying the Huntington's disease (HD) gene. Based on previous work, we hypothesized that HD gene carriers would show either neural or behavioral asymmetry between gain and loss learning.MethodsWe recruited 35 HD gene carriers, expected to demonstrate onset of motor symptoms in an average of 26 years, and 35 well-matched gene-negative control subjects. Participants were placed in a functional magnetic resonance imaging scanner, where they completed an RL task in which they were required to learn to choose between abstract stimuli with the aim of gaining rewards and avoiding losses. Task behavior was modeled using an RL model, and variables from this model were used to probe functional magnetic resonance imaging data.ResultsIn comparison with well-matched control subjects, gene carriers more than 25 years from motor onset showed exaggerated striatal responses to gain-predicting stimuli compared with loss-predicting stimuli (p = .002) in our RL task. Using computational analysis, we also found group differences in striatal representation of stimulus value (p = .0004). We found no group differences in behavior, cognitive scores, or caudate volumes.ConclusionsBehaviorally, gene carriers 9 years from predicted onset have been shown to learn better from gains than from losses. Our data suggest that a window exists in which HD-related functional neural changes are detectable long before associated behavioral change and 25 years before predicted motor onset. These represent the earliest functional imaging differences between HD gene carriers and control subjects.
| S-EPMC8423628 | biostudies-literature
Project description:Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disease caused by CAG repeats in exon 1 of the HTT gene. A hallmark of HD along with other psychiatric and neurodegenerative diseases is alteration in the neuronal circuitry and synaptic loss. Microglia and peripheral innate immune activation have been reported in pre-symptomatic HD patients; however, what "activation" signifies for microglial and immune function in HD and how it impacts synaptic health remains unclear. In this study we sought to fill these gaps by capturing immune phenotypes and functional activation states of microglia and peripheral immunity in the R6/2 model of HD at pre-symptomatic, symptomatic and end stages of disease. These included characterizations of microglial phenotypes at single cell resolution, morphology, aberrant functions such as surveillance and phagocytosis and their impact on synaptic loss in vitro and ex vivo in R6/2 mouse brain tissue slices. To further understand how relevant the observed aberrant microglial behaviors are to human disease, transcriptomic analysis was performed using HD patient nuclear sequencing data and functional assessments were conducted using induced pluripotent stem cell (iPSC)-derived microglia. Our results show temporal changes in brain infiltration of peripheral lymphoid and myeloid cells, increases in microglial activation markers and phagocytic functions at the pre-symptomatic stages of disease. Increases in microglial surveillance and synaptic uptake parallel significant reduction of spine density in R6/2 mice. These findings were mirrored by an upregulation of gene signatures in the endocytic and migratory pathways in disease-associated microglial subsets in human HD brains, as well as increased phagocytic and migratory functions of iPSC-derived HD microglia. These results collectively suggest that targeting key and specific microglial functions related to synaptic surveillance and pruning may be therapeutically beneficial in attenuating cognitive decline and psychiatric aspects of HD.
| S-EPMC10319581 | biostudies-literature
Project description:Brain microvascular endothelial cells (BMECs) are an essential component of the blood-brain barrier (BBB) that shields the brain against toxins and immune cells. While BBB dysfunction exists in neurological disorders, including Huntington's disease (HD), it is not known if BMECs themselves are functionally compromised to promote BBB dysfunction. Further, the underlying mechanisms of BBB dysfunction remain elusive given limitations with mouse models and post-mortem tissue to identify primary deficits. We undertook a transcriptome and functional analysis of human induced pluripotent stem cell (iPSC)-derived BMECs (iBMEC) from HD patients or unaffected controls. We demonstrate that HD iBMECs have intrinsic abnormalities in angiogenesis and barrier properties, as well as in signaling pathways governing these processes. Thus, our findings provide an iPSC-derived BBB model for a neurodegenerative disease and demonstrate autonomous neurovascular deficits that may underlie HD pathology with implications for therapeutics and drug delivery.
| S-EPMC5646270 | biostudies-literature
Project description:Gaucher's disease (GD) is an autosomal recessive disorder caused by mutations in the GBA1 gene, which encodes acid ?-glucocerebrosidase (GCase). Severe GBA1 mutations cause neuropathology that manifests soon after birth, suggesting that GCase deficiency interferes with neuronal development. We found that neuronopathic GD induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs) exhibit developmental defects due to downregulation of canonical Wnt/?-catenin signaling and that GD iPSCs' ability to differentiate to dopaminergic (DA) neurons was strikingly reduced due to early loss of DA progenitors. Incubation of the mutant cells with the Wnt activator CHIR99021 (CHIR) or with recombinant GCase restored Wnt/?-catenin signaling and rescued DA differentiation. We also found that GD NPCs exhibit lysosomal dysfunction, which may be involved in Wnt downregulation by mutant GCase. We conclude that neuronopathic mutations in GCase lead to neurodevelopmental abnormalities due to a critical requirement of this enzyme for canonical Wnt/?-catenin signaling at early stages of neurogenesis.
| S-EPMC5785733 | biostudies-literature
Project description:Cultured sensory neurons can exhibit complex activity patterns following stimulation in terms of increased excitability and interconnected responses of multiple neurons. Although these complex activity patterns suggest a network-like configuration, research so far had little interest in synaptic network formation ability of the sensory neurons. To identify interaction profiles of Dorsal Root Ganglia (DRG) neurons and explore their putative connectivity, we developed an in vitro experimental approach. A double transgenic mouse model, expressing genetically encoded calcium indicator (GECI) in their glutamatergic neurons, was produced. Dissociated DRG cultures from adult mice were prepared with a serum-free protocol and no additional growth factors or cytokines were utilized for neuronal sensitization. DRG neurons were grown on microelectrode arrays (MEA) to induce stimulus-evoked activity with a modality-free stimulation strategy. With an almost single-cell level electrical stimulation, spontaneous and evoked activity of GCaMP6s expressing neurons were detected under confocal microscope. Typical responses were analyzed, and correlated calcium events were detected across individual DRG neurons. Next, correlated responses were successfully blocked by glutamatergic receptor antagonists, which indicated functional synaptic coupling. Immunostaining confirmed the presence of synapses mainly in the axonal terminals, axon-soma junctions and axon-axon intersection sites. Concisely, the results presented here illustrate a new type of neuron-to-neuron interaction in cultured DRG neurons conducted through synapses. The developed assay can be a valuable tool to analyze individual and collective responses of the cultured sensory neurons.
| S-EPMC7928449 | biostudies-literature