Lipidomic profiling of mouse brain and human neuron cultures reveals a role for Mboat7 in mTOR-dependent neuronal migration

IF 15.8 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-01-01 DOI:10.1126/scitranslmed.adp5247

Isaac Tang, Ashna Nisal, Alex Reed, Timothy B. Ware, Anide Johansen, Maha S. Zaki, Benjamin F. Cravatt, Joseph G. Gleeson

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引用次数: 0

Abstract

Mutations in lipid regulator genes are a frequent cause of autism spectrum disorder, including those regulating phosphatidylinositol (PI) and phosphoinositide 3-kinase signaling. MBOAT7 encodes a key acyltransferase in PI synthesis and is mutated in an autism-related condition with neurodevelopmental delay and epilepsy. Using liquid chromatography–tandem mass spectrometry, we analyzed the PI-associated glycerolipidome in mice and humans during neurodevelopment and found dynamic regulation at times corresponding to neural apoptosis in the brains of Mboat7 knockout mice. Mboat7 function was necessary for polyunsaturated lipid synthesis and cortical neural migration, and loss resulted in massive accumulation of the precursor lysophosphatidylinositol and hyperactive mTOR signaling. Inhibiting mTOR signaling rescued migration defects. Our findings demonstrate roles for lipid remodeling during neurodevelopment and implicate lipid regulation in neuronal migration, revealing potential paths to treatment for MBOAT7 deficiency.

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.