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GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer's disease.

ABSTRACT: Biochemical, pathogenic, and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer's disease (AD) and Down's syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNAseq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with the Fe65-APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization and that lowering GSAP expression reduces pathological effects associated with AD.

SUBMITTER: Xu P

PROVIDER: S-EPMC8222926 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer's disease.

Xu Peng P Chang Jerry C JC Zhou Xiaopu X Wang Wei W Bamkole Michael M Wong Eitan E Bettayeb Karima K Jiang Lu-Lin LL Huang Timothy T Luo Wenjie W Xu Huaxi H Nairn Angus C AC Flajolet Marc M Ip Nancy Y NY Li Yue-Ming YM Greengard Paul P

The Journal of experimental medicine 20210622 8

Biochemical, pathogenic, and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer's disease (AD) and Down's syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNAseq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabol ...[more]

PMID: 34156424

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Project description:BackgroundAlzheimer's disease (AD) is a prevalent irreversible neurodegenerative condition marked by gradual cognitive deterioration and neuronal loss. The mammalian Ste20-like kinase (MST1)-Hippo pathway is pivotal in regulating cell apoptosis, immune response, mitochondrial function, and oxidative stress. However, the association between MST1 and mitochondrial function in AD remains unknown. Therefore, this study investigates the effect of MST1 on neuronal damage and cognitive impairment by regulating mitochondrial homeostasis in AD.MethodsIn this study, 4- and 7-month-old 5xFAD mice were selected to simulate the early and middle stages of AD, respectively; age-matched wild-type mice served as controls for comparative analysis. Adeno-associated virus (AAV) was injected into the hippocampus of mice. Four weeks post-injection, cognitive function, neuronal damage indicators, and mitochondrial morphology, dynamics, oxidative stress, ATP, and apoptosis-related indicators were evaluated. Additionally, RNA-sequencing was performed on the hippocampal tissue of 5xFAD mice and MST1-knockdown 5xFAD mice. Subsequently, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on differentially expressed genes to elucidate the potential mechanism of MST1. In vitro studies were performed to investigate the effects of MST1 on SH-SY5Y model cell viability and mitochondrial function and validate the potential underlying molecular mechanisms.ResultsMST1 overexpression accelerated neuronal degeneration and cognitive deficits in vivo while promoting oxidative stress and mitochondrial damage. Similarly, in vitro, MST1 overexpression facilitated apoptosis and mitochondrial dysfunction. MST1 knockdown and chemical inactivation reduced cognitive decline, mitochondrial dysfunction, and neuronal degeneration. Mechanistically, MST1 regulated the transcription of mitochondrial genes, including MT-ND4L, MT-ATP6, and MT-CO2, by binding to PGC1α. Moreover, MST1 influenced cellular oxidative stress through the PI3K-Akt-ROS pathway, ultimately disrupting mitochondrial homeostasis and mediating cell damage.ConclusionsCumulatively, these results suggest that MST1 primarily regulates mitochondrial DNA transcription levels by interacting with PGC1α and modulates cellular oxidative stress through the PI3K-Akt-ROS pathway, disrupting mitochondrial homeostasis. This discovery can be exploited to potentially enhance mitochondrial energy metabolism pathways by targeting MST1, offering novel potential therapeutic targets for treating AD.

Dataset Information

GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer's disease.

Publications

GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer's disease.

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