Title: Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology
Legend: Figure. SLC25A1 nTg mice display global proteomic changes in the hippocampus and cortex. (A) Volcano plots displaying all quantified proteins in SLC25A1 nTg hippocampus (left) and cortex (right) compared with WT controls. Statistically significant proteins are shown in green (99 in hippocampus and 227 in cortex; p < 0.05 via Fisher’s method) with all other proteins in grey. n = 4 male mice per genotype at 2-5 months of age. (B) Histogram and overlaid Gaussian distribution showing the distribution of all proteins’ log2 fold change from WT in hippocampus and cortex. A box and whisker plot is shown above with the box representing 25th/75th percentiles, middle line representing mean, and whiskers representing 1st/99th percentiles. ***p < 0.0005 via the Kolmogorov-Smirnov test. (C) Significantly changed proteins with overlap between the hippocampus and cortex. All proteins represented in green shown in panel A are included. The heat map shows the expression profile of the 13 overlapping proteins between hippocampus and cortex. (D) The fold enrichment of KEGG pathways determined from significantly changed proteins in the hippocampus and cortex compared with WT controls. The top 10 categories sorted by enrichment score are shown with a filtered FDR score of 0.05. (E) Gene-network plots of significantly changed proteins in the SLC25A1 nTg hippocampus and cortex. Plots constructed using an overrepresentation analysis using the GO cellular component function database. The dot size of each network category is scaled by the number of overlapping proteins within the category. The top 15 results are shown with a filtered FDR score of 0.05.
Citation: Rigby, M. J., Orefice, N. S., Lawton, A. J., Ma, M., Shapiro, S. L., Yi, S. Y., Dieterich, I. A., Frelka, A., Miles, H. N., Pearce, R. A., Yu, J. P. J., Li, L., Denu, J. M., & Puglielli, L. (2022). Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology. Brain: a journal of neurology, 145(2), 500–516. https://doi.org/10.1093/brain/awab295
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.
About the Lab: The Puglielli Lab’s research interests focus on molecular mechanisms of neurodevelopment and neurodegeneration. The laboratory employs a combination of biochemical, cellular, molecular, and genetic approaches in in vitro, ex vivo and in vivo models.
Investigator: Luigi Puglielli, MD, PhD