Luigi Puglielli, MD, PhD

Luigi Puglielli, MD, PhD Slide of the Week

Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation

Legend: AT-1 Tg animals display changes in neuronal morphology and imbalanced synaptic plasticity.

(A-D)  Morphological assessment of hippocampal neurons in culture. Phalloidin staining (upper panels) and unbiased computer-driven reconstruction (lower panels) of both WT and AT-1 Tg neurons (A and B) are shown. Sholl analysis (C) and spines quantification (D) are shown. Scale bar, 25 µm. Number of determinations for Sholl analysis: WT n=4; AT-1 Tg n= 5. Number of independent segments analyzed for spine density: WT n=16; AT-1 Tg n=36.

(E)  Golgi staining of the hippocampus from 6 month old WT and AT-1 Tg mice. Scale bar, 50 µm.

(F)  3xTBS induced LTP in WT and AT-1 Tg mice.

(G)  PP-LFS LTD in WT and AT-1 Tg mice.

(H-J) Western blot of selected relevant proteins. List and function of targeted proteins (H), quantification (I; n=5), and representative Western blots (J) are shown. GAPDH served as loading control.

*, P<0.05; **, P<0.005; #, P<0.0005. Student’s t-test and one-way ANOVA followed by Tukey-Kramer multiple comparisons test; for LTP and LTD, repeated measures ANOVA followed by Bonferroni post hoc tests. Bars represent mean + SD.

Citation: Hullinger R, Li M, Wang J, Peng Y, Dowell JA, Bomba-Warczak E, Mitchell HA, Burger C, Chapman ER, Denu JM, Li L, Puglielli L. (2016). Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation. Journal of Experimental Medicine, 27;213(7):1267-84. doi: 10.1084/jem.20151776.

Abstract: The import of acetyl-CoA into the lumen of the endoplasmic reticulum (ER) by AT-1/SLC33A1 regulates Nε-lysine acetylation of ER-resident and -transiting proteins. Specifically, lysine acetylation within the ER appears to influence the efficiency of the secretory pathway by affecting ER-mediated quality control. Mutations or duplications in AT-1/SLC33A1 have been linked to diseases such as familial spastic paraplegia, developmental delay with premature death, and autism spectrum disorder with intellectual disability. In the present study, we generated an AT-1 Tg mouse model that selectively overexpresses human AT-1 in neurons. These animals demonstrate cognitive deficits, autistic-like social behavior, aberrations in synaptic plasticity, an increased number of dendritic spines and branches, and widespread proteomic changes. We also found that AT-1 activity regulates acetyl-CoA flux causing epigenetic modulation of the histone epitope H3K27 and mitochondrial adaptation. In conclusion, our results indicate that increased expression of AT-1 can cause an autistic-like phenotype in mice by affecting key neuronal metabolic pathways.

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.

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