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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Min Ma  

LAB HEAD: Lingjun Li

PROVIDER: PXD026624 | Pride | 2021-08-26

REPOSITORIES: Pride