Decreased rates of cerebral protein synthesis measured in vivo in a mouse model of Tuberous Sclerosis Complex: unexpected consequences of reduced tuberin. Issue 5 (2nd April 2018)

• Record Type: Journal Article
• Authors: Saré, Rachel Michelle; Huang, Tianjian; Burlin, Tom; Loutaev, Inna; Smith, Carolyn Beebe
• Is Part Of: Journal of neurochemistry. Volume 145:Issue 5(2018)
• Page Start: 417
• Page End: 425
• Publication Date: 2018-04-02
• Subjects: autoradiography -- mTOR -- protein degradation -- protein synthesis -- translation -- tuberous sclerosis complex; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14311
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder affecting about 1 in 6000 people and is caused by mutations in either TSC1 or TSC2 . This disorder is characterized by increased activity of mammalian target of rapamycin complex 1 (mTORC1), which is involved in regulating ribosomal biogenesis and translation initiation. We measured the effects of Tsc2 haploinsufficiency ( Tsc2 +/− ) in 3‐month‐old male mice on regional rates of cerebral protein synthesis (rCPS) by means of the in vivo L‐[1‐ 14 C]leucine method. This quantitative autoradiographic method includes an estimate of the integrated specific activity of the tracer amino acid in brain tissue. The estimate accounts for recycling of unlabeled amino acids from tissue protein breakdown by means of a factor (λ) that was determined in control and Tsc2 +/− mice. The value of λ was higher in Tsc2 +/− mice, indicating that a greater fraction of leucine in the tissue precursor pool for protein synthesis is derived from the plasma compared to controls, consistent with reduced rates of protein degradation. We determined rCPS in freely moving, awake male Tsc2 +/− and control mice, and we used the determined values of λ in the calculation of rCPS. Unexpectedly, we found that rCPS were significantly decreased in 16 of the 17 brain regions analyzed in Tsc2 +/− mice compared to controls. Our results indicate a complex role of mTORC1 in the regulation of cerebral protein synthesis that has not been previously recognized. Abstract : Tuberous sclerosis complex (TSC) is a neurogenetic disorder caused by mutations in either TSC1 or TSC2 and characterized by epilepsy, intellectual disability, and autism spectrum disorders. TSC1 and TSC2 form a complex that inhibits mammalian target of rapamycin complex 1 (mTORC1), a key regulatory hub in cell signaling. Among other processes, mTORC1 regulates cellular protein synthesis. We hypothesized that rates of cerebral protein synthesis (rCPS) would be increased in mice haploinsufficient for Tsc2 . Contrary to our hypothesis, our results indicate that rCPS are decreased throughout the brain in haploinsufficient Tsc2 mice, suggesting a more complex role of mTORC1 in the regulation of cerebral protein synthesis than previously recognized.