Bibliographic Details
| Title: |
Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology. |
| Authors: |
Rigby, Michael J1,2,3 (AUTHOR), Orefice, Nicola Salvatore1,2 (AUTHOR), Lawton, Alexis J4 (AUTHOR), Ma, Min5 (AUTHOR), Shapiro, Samantha L1,2 (AUTHOR), Yi, Sue Y3 (AUTHOR), Dieterich, Inca A1,2,3 (AUTHOR), Frelka, Alyssa6 (AUTHOR), Miles, Hannah N5 (AUTHOR), Pearce, Robert A6 (AUTHOR), Yu, John Paul J7 (AUTHOR), Li, Lingjun5 (AUTHOR), Denu, John M4 (AUTHOR), Puglielli, Luigi1,2,8 (AUTHOR) lp1@medicine.wisc.edu |
| Source: |
Brain: A Journal of Neurology. Feb2022, Vol. 145 Issue 2, p500-516. 17p. |
| Subject Terms: |
*DENDRITIC spines, *AUTISM spectrum disorders, *MORPHOLOGY, *NEURONS, *WHITE matter (Nerve tissue), *ACETYLCOENZYME A |
| Abstract: |
N ε-lysine acetylation within the lumen of the endoplasmic reticulum is a recently characterized protein quality control system that positively selects properly folded glycoproteins in the early secretory pathway. Overexpression of the endoplasmic reticulum 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, which converts cytosolic citrate into acetyl-CoA. All three genes have been associated with autism spectrum disorder, suggesting that aberrant cytosolic-to-endoplasmic reticulum flux of acetyl-CoA can be a mechanistic driver for the development of autism spectrum disorder. We therefore generated a SLC25A1 neuron transgenic mouse with overexpression specifically in the forebrain neurons. The mice displayed autistic-like behaviours with a jumping stereotypy. They exhibited increased steady-state levels of citrate and acetyl-CoA, disrupted white matter integrity with activated microglia and altered synaptic plasticity and morphology. Finally, quantitative proteomic and acetyl-proteomic analyses revealed differential adaptations in the hippocampus and cortex. Overall, our study reinforces the connection between aberrant cytosolic-to-endoplasmic reticulum acetyl-CoA flux and the development of an autistic-like phenotype. [ABSTRACT FROM AUTHOR] |
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| Database: |
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