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Decreased rates of cerebral protein synthesis measured in vivo in a mouse model of Tuberous Sclerosis Complex: unexpected consequences of reduced tuberin.

Authors
  • Saré, Rachel Michelle1
  • Huang, Tianjian1
  • Burlin, Tom1
  • Loutaev, Inna1
  • Smith, Carolyn Beebe1
  • 1 Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
Type
Published Article
Journal
Journal of Neurochemistry
Publisher
Wiley (Blackwell Publishing)
Publication Date
Jan 24, 2018
Identifiers
DOI: 10.1111/jnc.14311
PMID: 29364507
Source
Medline
Keywords
License
Unknown

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.

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