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Increased expression of SLC25A1/CIC in the mouse results in an autistic-like phenotype with altered white matter microstructure and neuron morphology

ABSTRACT: Ne-lysine acetylation within the lumen of the endoplasmic reticulum (ER) is a recently characterized protein quality control system that positively selects properly folded glycoproteins in the early secretory pathway. Overexpression of the ER acetyl-CoA transporter AT-1 in mouse forebrain neurons results in increased dendritic branching, spine formation, and an autistic-like phenotype that is attributed to altered glycoprotein flux through the secretory pathway. AT-1 overexpressing neurons maintain the cytosolic pool of acetyl-CoA by upregulation of SLC25A1, the mitochondrial citrate/malate antiporter, and ATP citrate lyase (ACLY), which converts cytosolic citrate into acetyl-CoA. All three genes have been associated with autism spectrum disorder (ASD), suggesting that aberrant cytosolic to ER flux of acetyl-CoA can be a mechanistic driver for the development of ASD. We therefore generated a SLC25A1 neuron transgenic (nTg) mouse, which displayed autistic-like behaviors with a jumping stereotypy. The mice exhibited increased steady-state levels of citrate and acetyl-CoA, disrupted white matter integrity with activated microglia, and altered synaptic plasticity and morphology. Finally, acetylomic and proteomic analysis revealed differential adaptations in the hippocampus and cortex. Overall, our study reinforces the connection between aberrant cytosol-to-ER flux of acetyl-CoA flux and the development of an autistic-like phenotype.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Min Ma

LAB HEAD: Lingjun Li

PROVIDER: PXD025415 | Pride | 2022-02-26

REPOSITORIES: Pride

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SLC13A5/NaCT overexpression causes disrupted white matter integrity, synaptic dysfunction, and an autistic-like phenotype in the mouse

Project description:Endoplasmic-reticulum (ER)-based N-lysine acetylation is a positive selection marker for properly folded glycoproteins in the early secretory pathway, serving as an important protein quality control system. Excessive N-lysine acetylation within the ER via overexpression of the acetyl-CoA transporter AT-1 results in altered glycoprotein flux through the secretory pathway, which dramatically impacts dendritic branching and spine formation causing an autistic-like phenotype in the mouse. AT-1 works in concert with SLC25A1, the citrate/malate antiporter in the mitochondria, SLC13A5, the plasma membrane sodium/citrate synporter, and ATP citrate lyase (ACLY), the cytosolic enzyme that converts citrate into acetyl-CoA, in order to maintain the cytosolic-to-ER flux of acetyl-CoA. As such, we generated the SLC13A5 neuron transgenic (nTg) mouse with the hypothesis that increasing cytosolic citrate would impact acetyl-CoA flux into the ER and recapitulate the autistic-like AT-1 nTg model. Here, we demonstrated the SLC13A5 nTg mouse exhibits autistic-like behaviors with a jumping stereotypy. The mice displayed disrupted white matter integrity and altered synaptic structure and function. Finally, analysis of both the proteome and acetylome revealed unique adaptations in the hippocampus and cortex to SLC13A5 overexpression, implicating the importance of metabolic consequences of altered cytosolic citrate/acetyl-CoA availability in the neuron. Overall, our results corroborate the mechanistic link between aberrant intracellular citrate/acetyl-CoA flux and the development of an autistic-like phenotype.

2021-08-26 | PXD026624 | Pride

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ACLY and ACSS2 link nutrient-dependent chromatin accessibility to regulation of CD8 T cell effector responses [RNA-seq]

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ACLY and ACSS2 link nutrient-dependent chromatin accessibility to regulation of CD8 T cell effector responses

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