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GSAP regulates mitochondrial function through Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

ABSTRACT: GSAP regulates mitochondrial function through Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

PROVIDER: PRJNA663585 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12643473_1.fastq.gz	Fastqsanger.gz
	SRR12643473_2.fastq.gz	Fastqsanger.gz
	SRR12643474_1.fastq.gz	Fastqsanger.gz
	SRR12643474_2.fastq.gz	Fastqsanger.gz
	SRR12643475_1.fastq.gz	Fastqsanger.gz

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Project description:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late onset ALS. Although ALS results from MN’s death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a FUSR521H or a FUSP525L mutation and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette as described previously in our lab. Mutant and control iPSC differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Subsequent lipidomics studies demonstrated defects in myelin lipids, with a reduction of phospholipids in mutant OPCs. Among them, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most two abundant phospholipid in mammalian cells and regulate the mitochondria-associated ER membrane (MAM) integrity. Interestingly, FUSR521H mutant OPCs displayed a decrease in the PC/PE ratio, known to be associated with maintaining membrane (mitochondria) integrity. Proximity ligation assay further indicated that MAM was diminished in mutant OPCs. Moreover, mutant OPCs displayed stronger activation of unfolded protein response markers, a hallmark of increased susceptibility to endoplasmic reticulum (ER) stress, when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca2+ signaling from ER Ca2+ stores. Taken together, these results demonstrate that FUS mutant OPCs display defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and suppressed physiological Ca2+ signaling events.

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GSAP regulates mitochondrial function through Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

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