Project description:Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. We sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration, and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation, but not Tau pathology. Single-nucleus RNA-sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.

2023-09-21 | GSE217854 | GEO

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. Genome-wide localization of Histon K4 trimethylation in human iPSC and iPSC-derived neural stem cell using ChIP-seq

2013-01-01 | E-GEOD-34061 | biostudies-arrayexpress

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

Somatic Mutations and Cell Lineage in the Human Brain

Project description:<p>Genetic mutations causing human disease are conventionally thought to be inherited from one's parents and present in all somatic (body) cells. Increasingly however, somatic mutations are implicated in neurological diseases. Somatic mutations that arise during the cell divisions of prenatal brain development are inherited in clonal fashion and can cause neurodevelopmental diseases, even when present at low levels of mosaicism.</p> <p>In this study we use whole genome sequencing of single neurons and bulk tissue to identify somatic mutations in control, and some disease, brains to: 1) identify and catalogue the mutations which shape the somatic neuronal genome; 2) perform a cell lineage analysis of the adult human brain using clonal somatic mutations in cortical neurons; 3) determine patterns of somatic mutations at different ages and in aging related disease phenotypes; and 4) relate cell lineage patterns to cell phenotype in the human brain by separating neuronal, glial, and other cell types.</p>

| phs001485 | dbGaP

Homo sapiens

Project description:Single cell transcriptome analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns.

| PRJNA322355 | ENA

Single-cell Transcriptome Atlas of Testis Aging

Project description:Unhealthy aging of testis seriously affects fertility and life quality of older men, while its interventions depend on in-depth knowledge of the molecular and functional changes of various testicular cell types. Here, we profile human testicular single-cell transcriptomes from young adult, healthy old men and late-onset hypogonadism (LOH) patients, and identified the somatic cells underwent a greater change than germ cells.

2022-10-17 | GSE215754 | GEO

Somatic mutation load in clones of single human cells

Project description:Somatic mutation load in clones of single human cells

| PRJNA336367 | ENA