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Mitochondrial anomalies in induced pluripotent stem cells from Alzheimer’s disease cases with Presenilin 1 mutation

ABSTRACT: Mitochondrial anomalies in induced pluripotent stem cells from Alzheimer’s disease cases with Presenilin 1 mutation

PROVIDER: PRJNA1065335 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27561203_1.fastq.gz	Fastqsanger.gz
	SRR27561203_2.fastq.gz	Fastqsanger.gz
	SRR27561204_1.fastq.gz	Fastqsanger.gz
	SRR27561204_2.fastq.gz	Fastqsanger.gz
	SRR27561205_1.fastq.gz	Fastqsanger.gz

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Mitochondrial anomalies in induced pluripotent stem cells from Alzheimer’s disease cases with Presenilin 1 mutation

Project description:Presenilin 1 (PSEN1) is the most frequently mutated gene in early-onset sporadic and familial Alzheimer’s disease (FAD). The PSEN1 complex displays gamma-secretase activity and promotes cleavage of the C99-terminal fragment of the Amyloid Precursor Protein (APP) into the A42 peptide. PSEN1 is also involved in vesicle transport across ER and mitochondria in so called mitochondria associated membranes. We generated induced pluripotent stem cells (iPSCs) from 5 controls and 5 FAD cases carrying the PSEN1 A246E and L286V mutations. Unexpectedly, global gene expression profile analysis of FAD iPSCs revealed profound perturbation of mitochondrial, Golgi apparatus and ER pathways. PSEN1, APP and Nicastrin were highly expressed in iPSCs and PSEN1 localized to membrane-bound organelles. FAD iPSCs grown slower and showed elevated cell death together with abnormally high A42 secretion. Mitochondrial reactive oxygen species (ROS) were elevated in FAD iPSCs and treatment with a ROS scavenger significantly improved cell death, proliferation, and DNA damage. However, it could not improve the severe ATP deficit. Inhibition of gamma-secretase activity further exacerbated the overall FAD iPSC phenotype. Cortical neurons produced from the differentiation of FAD iPSCs showed Alzheimer’s pathology and TGFb pathway hyper-activation. PSEN1-mutant iPSCs may serve as a new model to perform genome-wide genetic screens and to study FAD pathophysiology and PSEN1 cellular function.

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Persistent epigenome anomalies in induced pluripotent stem cells from late-onset sporadic Alzheimer’s disease cases [RNA-seq]

Project description:Reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) resets the aging clock and is thought to erase other epigenomic marks. Here we show that iPSCs from late-onset sporadic Alzheimer’s disease (AD) cases retain epigenomic anomalies that supersede developmental defects, genomic instability, and neurodegeneration. When compared to iPSCs from elderly controls, AD iPSCs display reduced BMI1 and KDM5A expression, a more relax heterochromatin, and an altered DNA methylome. AD neuroepithelial cells show lesser efficient neural induction and forebrain specification, together with perturbed WNT signaling. They also present a unique genomic instability phenotype characterized by replication stress and DNA damage at the nuclear envelope-associated heterochromatin. BMI1 knockdown in control neuroepithelial cells phenocopied the AD-related pathologies. Long-term AD neuronal cultures show a dedifferentiation and loss-of-cell identity phenotype resembling epigenome erosion. BMI1 overexpression in AD neurons mitigates amyloid accumulation, tau pathology, heterochromatin fragmentation and G4 DNA induction. These findings implicate persistent epigenomic anomalies or uncharacterized genetic alterations working in trans on the epigenome in AD iPSCs, which could have broader implications in our understanding of the disease origin and pathophysiological mechanisms.

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Persistent epigenome anomalies in induced pluripotent stem cells from late-onset sporadic Alzheimer’s disease cases

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aCGH analysis of familial Alzheimer’s disease with presenilin 2 mutation patient-specific induced pluripotent stem cells

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Project description:Persistent epigenome anomalies in induced pluripotent stem cells from late-onset sporadic Alzheimer’s disease cases [RNA-seq]

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