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Neurodevelopmental Defects and Neurodegenerative Phenotypes in Human Brain Organoids Carrying Parkinson Disease-Linked DNAJC6 Mutations

ABSTRACT: In this study, human isogenic model of juvenile onset PD caused by DNAJC6 mutation were made. Human ESCs edited using CRISPR-Cas9 to make deleterious DNAJC6 mutation was induced to human midbrain like organoid (hMLO) for studying the mechanism of DNAJC6 deleterious mutation in causing PD

ORGANISM(S): Homo sapiens

PROVIDER: GSE151190 | GEO | 2020/05/27

REPOSITORIES: GEO

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Neurodevelopmental Defects and Neurodegenerative Phenotypes in Human Brain Organoids Carrying Parkinson Disease-Linked DNAJC6 Mutations

Project description:Neurodevelopmental Defects and Neurodegenerative Phenotypes in Human Brain Organoids Carrying Parkinson Disease-Linked DNAJC6 Mutations

| PRJNA635098 | ENA

Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson's disease-linked <i>DNAJC6</i> mutations.

Project description:Loss-of-function mutations of DNAJC6, encoding HSP40 auxilin, have recently been identified in patients with early-onset Parkinson's disease (PD). To study the roles of DNAJC6 in PD pathogenesis, we used human embryonic stem cells with CRISPR-Cas9-mediated gene editing. Here, we show that DNAJC6 mutations cause key PD pathologic features, i.e., midbrain-type dopamine (mDA) neuron degeneration, pathologic α-synuclein aggregation, increase of intrinsic neuronal firing frequency, and mitochondrial and lysosomal dysfunctions in human midbrain-like organoids (hMLOs). In addition, neurodevelopmental defects were also manifested in hMLOs carrying the mutations. Transcriptomic analyses followed by experimental validation revealed that defects in DNAJC6-mediated endocytosis impair the WNT-LMX1A signal during the mDA neuron development. Furthermore, reduced LMX1A expression during development caused the generation of vulnerable mDA neurons with the pathologic manifestations. These results suggest that the human model of DNAJC6-PD recapitulates disease phenotypes and reveals mechanisms underlying disease pathology, providing a platform for assessing therapeutic interventions.

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CNV analysis for Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations

Project description:Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease in disease relevant cells, as well as a promising source for cell replacement therapies for degenerative diseases. However one of the crucial limitations before realizing the full promise of this “disease in a dish” approach has been the inability to do controlled experiments under genetically defined conditions. This is particularly relevant for disorders with long latency periods, such as Parkinson’s disease (PD), where in vitro phenotypes of patient-derived iPSCs are predicted to be subtle and susceptible to significant epistatic effects of genetic background variations. By combining zinc-finger nuclease (ZFN)-mediated genome editing and iPSC technology we provide a generally applicable solution to this key problem by generating isogenic pairs of disease and control human embryonic stem cells (hESCs) and hiPSCs lines that differ exclusively at a susceptibility variant for PD by modifying a single point mutation (A53T) in the ?-synuclein gene. The robust capability to genetically correct disease causing point mutations in patient-derived hiPSCs represents not only a significant progress for basic biomedical research but also a major advancement towards hiPSC-based cell replacement therapies using autologous cells. ZFN-mediated genome edited human iPS cells or ES cells were assayed for genomic variation

2011-07-25 | E-GEOD-29772 | biostudies-arrayexpress

Gene Expression Data for Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations

Project description:Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease in disease relevant cells, as well as a promising source for cell replacement therapies for degenerative diseases. However one of the crucial limitations before realizing the full promise of this “disease in a dish” approach has been the inability to do controlled experiments under genetically defined conditions. This is particularly relevant for disorders with long latency periods, such as Parkinson’s disease (PD), where in vitro phenotypes of patient-derived iPSCs are predicted to be subtle and susceptible to significant epistatic effects of genetic background variations. By combining zinc-finger nuclease (ZFN)-mediated genome editing and iPSC technology we provide a generally applicable solution to this key problem by generating isogenic pairs of disease and control human embryonic stem cells (hESCs) and hiPSCs lines that differ exclusively at a susceptibility variant for PD by modifying a single point mutation (A53T) in the α-synuclein gene. The robust capability to genetically correct disease causing point mutations in patient-derived hiPSCs represents not only a significant progress for basic biomedical research but also a major advancement towards hiPSC-based cell replacement therapies using autologous cells. ZFN-mediated genome edited human iPS cells or ES cells were assayed for gene expression

2011-07-25 | E-GEOD-29773 | biostudies-arrayexpress

Human microglia carrying an early-onset Parkinson’s disease mutation display cell-autonomous disease-relevant phenotypes that may worsen neuronal damage

Project description:Parkinson’s disease (PD) is characterized by the aggregation of α-synuclein into Lewy bodies and Lewy neurites in the brain. Microglia-driven neuroinflammation may contribute to neuronal death in PD, however the exact role of microglia remains unclear and has been understudied. The A53T mutation in the gene coding for α-synuclein has been linked to early-onset PD, and exposure to A53T-mutant human α-synuclein increases the potential for inflammation of murine microglia. To date, its effect has not been studied in human microglia. We aimed to study the impact of the A53T mutation on human microglia developed in a physiologically relevant context Here, we used 2-dimensional cultures of human iPSC-derived microglia and transplantation of these cells into the mouse brain to assess the effects of the A53T mutation on human microglia. We found that A53T-mutant human microglia had an intrinsically increased propensity towards pro-inflammatory activation upon inflammatory stimulus. Additionally, A53T mutant microglia showed increased oxidative stress, with a strong decrease in catalase expression in non-inflammatory conditions. Together, these results indicate that A53T mutant human microglia display cell-autonomous phenotypes that may worsen neuronal damage in early-onset PD.

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Project description:Biallelic genetic variants in N-acetylneuraminic acid synthase (NANS), a critical enzyme in endogenous sialic acid biosynthesis, are clinically associated with neurodevelopmental disorders. However, the mechanism underlying the neuropathological consequences has remained elusive. Here, we discovered that NANS mutation resulted in absence of both sialic acid and protein polysialylation in the cortical organoids and significantly reduced the proliferation and expansion of neural progenitors. NANS mutation dysregulated neural migration and differentiation, disturbed synapse formation, and weakened neuronal activity. Single-cell RNA sequencing revealed that NANS loss-of-function markedly altered transcriptional programs involved in neuronal differentiation and ribosomal biogenesis in various neuronal cell types. Similarly, Nans heterozygous mice exhibited impaired cortical neurogenesis and neurobehavioral deficits. Collectively, our findings reveal a crucial role of NANS-mediated endogenous sialic acid biosynthesis in regulating multiple features of human cortical development, thus linking NANS mutation with its clinically relevant neurodevelopmental disorders.

2023-06-26 | GSE233460 | GEO

Single cell profile of human iPSC-derived midbrain organoids from healthy individual, Parkinson disease patient harboring a Miro1R272Q mutation and its respective isogenic control

Project description:Midbrain organoids are 3D in vitro models, which represent the human midbrain and can be used as Parkinson's disease (PD) models. In the current study, we used single cell RNA sequencing (scRNA-seq) to investigate the effect of a novel mutation in the RhoT1 gene (Miro1 R272Q) in the PD pathology, and how it affect the dopaminergic neuron population present in the model.

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RNA-seq of retinal organoids differentiated from hESCs carrying mutations in the RB1 gene

Project description:hESC lines carrying deleterious mutations in the RB1 gene in heterozygous and homozygous state were generated by genome-editing based on CRISPR/Cas9. Parental cell line and genome-edited cell lines were differentiated into retinal organoids for 152 days based on the Protocol published by Döpper et al., Current protocols, PMID: 32956559. Briefly, single cells were reaggregated in presence of dual SMAD and WNT-inhibition; retinal tissue became visible from day 12 onward. BMP4-induction and addition of small molecules CHIR99021 and SU5402 directed differentiation towards retina and retinal pigment epithelium. Long-term differentiation was carried out in the presence of 10% FBS, taurine and retinoic acids. Organoids were collected at indicated time points and either embedded for cryosectioning and immunostaining or frozen at -80°C for RNA preparation.

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Inefficient DNA repair is an aging-related modifier of Parkinson disease

Project description:The underlying relation between Parkinson disease (PD) etiopathology and its major risk factor, aging, is largely unknown. The nature of the specific age-related mechanisms promoting PD onset is experimentally difficult to elucidate because aging is a highly complex process contributed by multiple factors. Recent evidence, however, established a strong and causative link between genome stability and aging. To investigate a possible nexus between DNA damage accumulation, aging, and PD we examined DNA repair pathways associated with aging in laboratory animal models and human cases. We demonstrate that dermal fibroblasts from PD patients display flawed nucleotide excision repair (NER) capacity and that NER-defective mice exhibit typical PD-like pathological alterations, including decreased dopaminergic innervation in the striatum, increased phospho-synuclein levels, and defects in mitochondrial respiration. NER mouse mutants are also more sensitive to the prototypical PD toxin MPTP and their transcriptomic landscape shares important similarities with that of PD patients. Overall, our results demonstrate that specific defects in DNA repair impact the dopaminergic system, are associated with human PD pathology, and might therefore constitute a novel risk factor for PD by affecting the aging process.

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Knocking out C9ORF72 exacerbates axonal trafficking defects associated with hexanucleotide repeat expansion and reduces levels of heat shock proteins I

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