title: Inborn Errors of Long-Chain Fatty Acid β-Oxidation Link Neural Stem Cell Self-Renewal to Autism.
abstract: Inborn errors of metabolism (IEMs) occur with high incidence in human populations. Especially prevalent among these are inborn deficiencies in fatty acid β-oxidation (FAO), which are clinically associated with developmental neuropsychiatric disorders, including autism. We now report that neural stem cell (NSC)-autonomous insufficiencies in the activity of TMLHE (an autism risk factor that supports long-chain FAO by catalyzing carnitine biosynthesis), of CPT1A (an enzyme required for long-chain FAO transport into mitochondria), or of fatty acid mobilization from lipid droplets reduced NSC pools in the mouse embryonic neocortex. Lineage tracing experiments demonstrated that reduced flux through the FAO pathway potentiated NSC symmetric differentiating divisions at the expense of self-renewing stem cell division modes. The collective data reveal a key role for FAO in controlling NSC-to-IPC transition in the mammalian embryonic brain and suggest NSC self renewal as a cellular mechanism underlying the association between IEMs and autism.
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, TX 77843, USA. Electronic address: zxie@tamhsc.edu.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Jones
authors.affiliation: Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Jude T
authors.initials: JT
authors.lastname: Deeney
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, TX 77843, USA.
authors.forename: Seong Kwon
authors.initials: SK
authors.lastname: Hur
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, College Station, TX 77843, USA.
authors.forename: Vytas A
authors.initials: VA
authors.lastname: Bankaitis
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism; D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism* / Q000473:pathology*; D055162:Biocatalysis / Q000187:drug effects; D019748:Carbon-Carbon Double Bond Isomerases / Q000378:metabolism; D002331:Carnitine / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000172:deficiency / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D004746:Enoyl-CoA Hydratase / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D066292:Lipid Droplets / Q000187:drug effects / Q000378:metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D019579:Neocortex / Q000196:embryology / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D019998:Racemases and Epimerases / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D034741:RNA, Small Interfering; C038784:fatty acid oxidation complex; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; D002334:Carnitine O-Palmitoyltransferase; D004746:Enoyl-CoA Hydratase; D019998:Racemases and Epimerases; D019748:Carbon-Carbon Double Bond Isomerases; D002331:Carnitine
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