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Progressive degeneration of human neural stem cells caused by pathogenic LRRK2

ABSTRACT: Aging and its physiological manifestations have been correlated with adult stem cell exhaustion and a failure to maintain tissue homeostasis1-10. Since multiple morphological cellular defects are associated with aging-related disorders, we hypothesized that late onset disorders might be linked to adult stem cell abnormalities compromising cellular function over time. Our work shows that a dominant G2019S mutation in the human LRRK2 gene, which is associated with central nervous system disorders, including Parkinson’s disease, the second most prevalent neurodegenerative disease in the aging population, causes alterations in neural stem cell homeostasis in aging-related cellular contexts. They include disruption of the nuclear architecture, deficiencies in clonal expansion and alterations in neural differentiation assays as well as an increased susceptibility to proteasomal stress. These phenotypic changes are dependent on differential kinase activity manifested during cellular passaging. Our studies might open new venues for studying the influence of aging in neural stem cell dependent processes, such as cognitive impairments, in the degenerating diseased brain. Genome-wide localization of Histon K4 trimethylation in human iPSC and iPSC-derived neural stem cell using ChIP-seq

ORGANISM(S): Homo sapiens

SUBMITTER: Ulrich Wagner

PROVIDER: E-GEOD-34061 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Progressive degeneration of human neural stem cells caused by pathogenic LRRK2

Project description:Aging and its physiological manifestations have been correlated with adult stem cell exhaustion and a failure to maintain tissue homeostasis1-10. Since multiple morphological cellular defects are associated with aging-related disorders, we hypothesized that late onset disorders might be linked to adult stem cell abnormalities compromising cellular function over time. Our work shows that a dominant G2019S mutation in the human LRRK2 gene, which is associated with central nervous system disorders, including Parkinson’s disease, the second most prevalent neurodegenerative disease in the aging population, causes alterations in neural stem cell homeostasis in aging-related cellular contexts. They include disruption of the nuclear architecture, deficiencies in clonal expansion and alterations in neural differentiation assays as well as an increased susceptibility to proteasomal stress. These phenotypic changes are dependent on differential kinase activity manifested during cellular passaging. Our studies might open new venues for studying the influence of aging in neural stem cell dependent processes, such as cognitive impairments, in the degenerating diseased brain.

2013-01-01 | GSE34061 | GEO

Gene expression analysis of human iPSC generated from pathogenic LRRK2 (G2019S) mutation bearing patients

Project description:Genetic mutations on leucine-rich repeat kinase 2 (LRRK2) have been associated with an increased risk of Parkinson's disease. The Gly2019Ser (G2019S) mutation on LRRK2 gene is a relatively common cause of familial Parkinson's disease in Caucasian population. In this study, we generated human induced pluripotent stem cell (iPSC) lines from LRRK2 (G2019S) bearing patient fibroblasts by cell reprogramming. We performed global gene expression profiling of LRRK2 (G2019S) heterozygous and homozygous patient iPSC lines, and the corresponding fibroblast lines they originated from. An age-matched wildtype human fibroblast line and H1 human embryonic stem cell (ESC) line were used as controls. Microarray gene expression profiling was done to: (1) Compare global gene expression differences between wildtype fibroblasts and fibroblasts from patients bearing homozygous and heterozygous LRRK2 (G2019S) mutation; (2) Compare global gene expression differences between wildtype iPSC and iPSC generated from LRRK2 (G2019S) homozygous and heterozygous patients; (3) Check that all iPSC generated from wildtype and patients fibroblasts are in fact similar to human pluripotent ESC.

2012-10-17 | E-GEOD-33298 | biostudies-arrayexpress

Expression data from human induced pluripotent stem cell derived NSCs and striatal-like cells

Project description:Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded stretch of CAG trinucleotide repeats that results in neuronal dysfunction and death. We made induced pluripotent stem cell (iPSC) lines from HD patients and controls. Though no obvious effects of the CAG expansion on reprogramming or subsequent neural stem cell (NSC) production were seen, HD-NSCs showed CAG expansion-associated gene expression patterns and, upon differentiation, changes in electrophysiology, metabolism, cell adhesion, and ultimately an increased risk of cell death for both medium and longer CAG repeat expansions, with some deficits greater in cells from longer repeat HD NSCs. The HD180 lines were more vulnerable than control lines to cellular stressors and BDNF withdrawal using a range of assays across consortium laboratories. This HD iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in HD and provides a novel human stem cell platform for screening new candidate therapeutics. 8 NSC samples (5 HD, 3 control), of which 3 were run as replicates (2HD, 1 control), and 5 striatal-like samples (3 HD, 2 control) Contributor: The HD iPS consortium

2012-04-24 | E-GEOD-37517 | biostudies-arrayexpress

GENETIC CORRECTION OF HUNTINGTON'S DISEASE PHENOTYPES IN INDUCED PLURIPOTENT STEM CELLS

Project description:Huntington's Disease (HD) is caused by a CAG expansion in the huntingtin gene. Expansion of the polyglutamine tract in the huntingtin protein results in massive cell death in the striatum of HD patients. We report that human induced pluripotent stem cells (iPSCs) derived from HD patient fibroblasts can be corrected by replacing the expanded CAG repeat with a normal repeat using homologous recombination, and that the correction persists in iPSC differentiation into DARPP-32 positive neurons in vitro and vivo. Further, correction of the HD-iPSCs normalized pathogenic HD signaling pathways (cadherin, TGF-?, BNDF, caspase activation), and reversed disease phenotypes such as susceptibility to cell death and altered mitochondrial bioenergetics in neural stem cells. The ability to make patient-specific, genetically corrected iPSCs from HD patients will provide relevant disease models in identical genetic backgrounds and is a critical step for the eventual use of these cells in cell replacement therapy. 16 experimental samples were used overall. There were 8 replicates per group, with one group being the control, and the other being the experimental. Comparison was carried out on the Nimblegen platform.

2012-06-14 | E-GEOD-37547 | biostudies-arrayexpress

A mechanism for the segregation of age in mammalian neural stem cells

Project description:Across life neural stem cells (NSCs) generate new neurons in the mammalian brain through asymmetric neurogenic and self-renewing cell divisions. However, the cellular mechanisms underlying NSC asymmetry remain unknown. Using fluorescence loss in photobleaching (FLIP) we here show that NSCs in vitro and within the developing forebrain generate a lateral diffusion barrier during cell division resulting in asymmetric segregation of cellular components. The strength of the diffusion barrier is dynamically regulated with age and depends on the proper function of lamin-associated nuclear envelope constituents. Strikingly, age-associated or experimental impairment of the diffusion barrier disrupts asymmetric segregation of damaged proteins, a product of aging. Thus, the data presented here identify a mechanism how age is asymmetrically distributed during somatic stem cell division. For microarray analysis we analysed gene expression in cells derived from the hippocampi of 6 week old (young) or 9 month old (old) male C57BL/6JRj mice. 6 samples were analyzed YoungNSC, 3 replicates OldNSC, 3 replicates

2015-09-22 | E-GEOD-61367 | biostudies-arrayexpress

Time line RNAseq of iPSC-derived neurons from ASD and control subjects.

Project description:To comprehensively profile early neurodevelopmental alterations in individuals with ASD, we harnessed a time series approach to monitor patient-derived induced pluripotent stem cells (iPSCs) throughout the recapitulation of cortical development. This dataset consists of patient derived neurons that go through all consecutive developmental stages (NSC-derived neurons) as well as a comparative set of iPSC-iNs (neurons generated from the same patients that bypass early NSC-like stages using an Ngn2-transgene approach). For this, we first used fluorescence-activated cell sorting (FACS) to purify a homogeneous population of NSCs based on the expression of the cell-surface markers CD184+/CD271-/CD44-/CD24-/CD15+. To trace ASD and control neurons over time, we performed a series of retroviral lineage-tracing experiments to trace the progenies of dividing NSCs using a retroviral vector expressing a membrane-tagged enhanced green fluorescent protein (eGFP) (CAG::LckN-eGFP). As differentiating neurons express PSA-NCAM on the cell surface, we established a FACS-based protocol for purification of defined subpopulations of retrovirally labeled eGFP+/PSA-NCAM+ double-positive neurons after 2, 4, 7 and 14 days of differentiation. IPSCs were sorted based on the expression of SSEA-4 and TRA1-81 and maturing iPSC-iNs were collected at the indicated days after induction by sorting for eGFP (indicative for the Ngn2 transgene)- and PSA-NCAM-positive cells.

2019-01-07 | E-MTAB-6018 | biostudies-arrayexpress

Transcriptome analysis of isogenic Neural stem cell for LRRK2 G2019S mutation.

Project description:We report the transcriptome data produced from isogenic neural stem cells with normal LRRK2 gene, or LRRK2 G2019S mutation. After gene correction from patient-derived iPSCs with LRRK2 G2019S, the isogenic lines were diffrentiated toward neural stem cells. To reflect on aging effect, theses cells were harvested to the early (passage number 1) or late stage (passage number 13), without replicate. Also, they were prepared at the early stage (passage number 3), triplicate.

2021-09-08 | GSE183499 | GEO

Genome-wide expression profiling of the LRRK2-G2019S mutation in hNES cells

Project description:Parkinson’s disease (PD) has a neuro-developmental component with multiple genetic predispositions. The most prevalent mutation, LRRK2-G2019S is linked to familial and sporadic PD. Based on the multiple origins of PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patient genetic background act as susceptibility factors for developing PD. To assess the developmental component of LRRK2-G2019S pathogenesis, we used 19 human iPSC-derived neuroepithelial stem cell lines (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal. Within patients, phenotypes were only partly LRRK2-G2019S dependent, suggesting Parkinson’s disease (PD) has a neuro-developmental component with multiple genetic predispositions. The most prevalent mutation, LRRK2-G2019S is linked to familial and sporadic PD. Based on the multiple origins of PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patient genetic background act as susceptibility factors for developing PD. To assess the developmental component of LRRK2-G2019S pathogenesis, we used 19 human iPSC-derived neuroepithelial stem cell lines (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal. Within patients, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. We identified Serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the abberant phenotypes. Its enzymatic product, D-Serine, rescued altered NESC renewal. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment.

2018-03-07 | GSE101534 | GEO

Gene expression analysis of human iPSC generated from pathogenic LRRK2 (G2019S) mutation bearing patients

2012-10-17 | GSE33298 | GEO

Human iPSC-based Modeling of Late-Onset Disease using Progerin-induced Aging

Project description:Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) sets their identity back to an embryonic age. This presents a fundamental hurdle for modeling late-onset disorders using iPSC-derived cells. We therefore developed a strategy to induce age-like features in multiple iPSC-derived lineages and tested its impact on modeling Parkinson’s disease (PD). We first describe markers that predict fibroblast donor age and observed the loss of these age-related markers following iPSC induction and re-differentiation into fibroblasts. Remarkably, age-related markers were readily induced in iPSC-derived fibroblasts or neurons following exposure to progerin including dopamine neuron-specific phenotypes such as neuromelanin accumulation. Induced aging in PD-iPSC-derived dopamine neurons revealed disease phenotypes requiring both aging and genetic susceptibility such as frank dendrite degeneration, progressive loss of tyrosine-hydroxylase expression and enlarged mitochondria or Lewy body-precursor inclusions. Our study presents a strategy for inducing age-related cellular properties and enables the modeling of late-onset disease features. Induced pluripotent stem cell-derived midbrain dopamine neurons from a young and old donor overexpressing either GFP or Progerin.

2014-01-23 | E-GEOD-52431 | biostudies-arrayexpress

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