Decreased protein synthesis in a mouse model of Tuberous Sclerosis Complex: unexpected consequences of mTORC1 activation

Monday, September 22, 2014 — Poster Session I
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NIMH	NEURO-25

Authors

• R.M. Reith
• T Huang
• M Qin
• C.B. Smith

Abstract

Tuberous Sclerosis Complex (TSC) is an autosomal dominant neurogenetic disorder affecting about 1 in 6,000 people, leading to benign growths throughout the brain and other vital organs. TSC usually has effects on the central nervous system manifested by a high incidence of seizures, intellectual disability, and autism. TSC is caused by mutations in either TSC1 or TSC2, which encode for proteins that inhibit mammalian target of rapamycin complex 1 (mTORC1), a central regulator of ribosomal biogenesis and translation initiation. Therefore, we hypothesized that haploinsufficiency of Tsc2 (Tsc2+/-) in mice would lead to increased regional rates of cerebral protein synthesis (rCPS). We measured rCPS in freely-moving awake male Tsc2+/- mice (age 3 months) with the quantitative autoradiographic L-[1-14C]leucine method. We compared rCPS in 16 brain regions in 11 Tsc2+/- mice with 10 control mice assuming that the fraction of unlabeled amino acids derived from protein breakdown in the tissue in the precursor amino acid pool for protein synthesis was similar in both genotypes. Unexpectedly, we found statistically significant decreased rates of protein synthesis in many brain regions, including hippocampus (-17%), cortex (-16.5%), thalamus (-16%), and hypothalamus (-20%). These results suggest a possible novel role/ regulation of protein synthesis in the brain.

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