SLC13A5/sodium-citrate co-transporter overexpression causes disrupted white matter integrity and an autistic-like phenotype

Michael J Rigby; Nicola Salvatore Orefice; Alexis J Lawton; Min Ma; Samantha L Shapiro; Sue Y Yi; Inca A Dieterich; Alyssa Frelka; Hannah N Miles; Robert A Pearce; John Paul J Yu; Lingjun Li; John M Denu; Luigi Puglielli

doi:10.1093/braincomms/fcac002

SLC13A5/sodium-citrate co-transporter overexpression causes disrupted white matter integrity and an autistic-like phenotype

Brain Commun. 2022 Jan 5;4(1):fcac002. doi: 10.1093/braincomms/fcac002. eCollection 2022 Feb.

Authors

Michael J Rigby^{1

2

3}, Nicola Salvatore Orefice^{1

2}, Alexis J Lawton⁴, Min Ma⁵, Samantha L Shapiro^{1

2}, Sue Y Yi³, Inca A Dieterich^{1

2

3}, Alyssa Frelka⁶, Hannah N Miles⁵, Robert A Pearce⁶, John Paul J Yu⁷, Lingjun Li⁵, John M Denu⁴, Luigi Puglielli^{1

2

8}

Affiliations

¹ Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
² Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA.
³ Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁴ Department of Biomolecular Chemistry and the Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
⁵ School of Pharmacy and Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁶ Department of Anesthesiology, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁷ Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
⁸ Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, WI 53705, USA.

Abstract

Endoplasmic reticulum-based N ^ɛ-lysine acetylation serves as an important protein quality control system for the secretory pathway. Dysfunctional endoplasmic reticulum-based acetylation, as caused by overexpression of the acetyl coenzyme A transporter AT-1 in the mouse, results in altered glycoprotein flux through the secretory pathway and an autistic-like phenotype. AT-1 works in concert with SLC25A1, the citrate/malate antiporter in the mitochondria, SLC13A5, the plasma membrane sodium/citrate symporter and ATP citrate lyase, the cytosolic enzyme that converts citrate into acetyl coenzyme A. Here, we report that mice with neuron-specific overexpression of SLC13A5 exhibit autistic-like behaviours with a jumping stereotypy. The mice displayed disrupted white matter integrity and altered synaptic structure and function. Analysis of both the proteome and acetyl-proteome revealed unique adaptations in the hippocampus and cortex, highlighting a metabolic response that likely plays an important role in the SLC13A5 neuron transgenic phenotype. Overall, our results support a mechanistic link between aberrant intracellular citrate/acetyl coenzyme A flux and the development of an autistic-like phenotype.

Keywords: AT-1; SLC13A5; acetyl-CoA; citrate; lysine acetylation.

Published by Oxford University Press on behalf of the Guarantors of Brain 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Abstract

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