title: Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation.
abstract: The import of acetyl-CoA into the lumen of the endoplasmic reticulum (ER) by AT-1/SLC33A1 regulates Nε-lysine acetylation of ER-resident and -transiting proteins. Specifically, lysine acetylation within the ER appears to influence the efficiency of the secretory pathway by affecting ER-mediated quality control. Mutations or duplications in AT-1/SLC33A1 have been linked to diseases such as familial spastic paraplegia, developmental delay with premature death, and autism spectrum disorder with intellectual disability. In this study, we generated an AT-1 Tg mouse model that selectively overexpresses human AT-1 in neurons. These animals demonstrate cognitive deficits, autistic-like social behavior, aberrations in synaptic plasticity, an increased number of dendritic spines and branches, and widespread proteomic changes. We also found that AT-1 activity regulates acetyl-CoA flux, causing epigenetic modulation of the histone epitope H3K27 and mitochondrial adaptation. In conclusion, our results indicate that increased expression of AT-1 can cause an autistic-like phenotype by affecting key neuronal metabolic pathways.
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Rikki
authors.initials: R
authors.lastname: Hullinger
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Mi
authors.initials: M
authors.lastname: Li
authors.affiliation: Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53705 School of Pharmacy and Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Jingxin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: James A
authors.initials: JA
authors.lastname: Dowell
authors.affiliation: Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53705 Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705 Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Ewa
authors.initials: E
authors.lastname: Bomba-Warczak
authors.affiliation: Rodent Models Core, Waisman Center, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Mitchell
authors.affiliation: Department of Neurology, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Corinna
authors.initials: C
authors.lastname: Burger
authors.affiliation: Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705 Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chapman
authors.affiliation: Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: John M
authors.initials: JM
authors.lastname: Denu
authors.affiliation: School of Pharmacy and Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Lingjun
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705 Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, WI 53705 lp1@medicine.wisc.edu.
authors.forename: Luigi
authors.initials: L
authors.lastname: Puglielli
mesh_terms: D000105:Acetyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049229:Dendritic Spines / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044127:Epigenesis, Genetic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype
chemical_list: D006657:Histones; D026901:Membrane Transport Proteins; C484549:SLC33A1 protein, human; C105440:Slc33a1 protein, mouse; D000105:Acetyl Coenzyme A