Sluggish mTOR signaling to stimulate Roberts Syndrome

PLoS Genetics published a research, conducted by the experts at Stowers Institute of Medical Research. It reports that a notable signaling pathway which drives cellular growth is inhibited in cohesinopathy also known as Roberts syndrome (RBS). The study basically links dampened mTOR signaling with the development of RBS.

Cohesinopathy or Roberts syndrome is a developmental disease. The affected individual suffers severe consequences like,

  • Intellectual disabilities
  • Limb shortening
  • Cranio-facial anomalies
  • Slowed growth

The researchers were already aware of the mutations underlying the syndrome. However, they had little understanding of the downstream signals that are disrupted in these conditions. This respective research analyzes patient cells and zebrafish models of RBS. It shows that L-leucine can jump-start the sluggish mTOR signaling pathway which partially rescues defects associated with the disease at both the cellular and organism level.

Mutations in the genes encoding cohesins may result in cohesinopathies. Cohesins form ring-shaped protein complexes for genome organization. The human gene ESCO2 encodes an enzyme that chemically modifies cohesins. Inactivation of this gene may result in RBS.

A 2009 research at Stowers Institute reported that the yeast homolog of ESCO2 plays an eminent role in the formation of the nucleolus where ribosomes are produced.  Ribosomes are large molecular factories made of RNA and protein and they work to manufacture new proteins according to the instructions carried in mRNA.

The research team suspected that nucleolar organization might be an evolutionarily conserved function for cohesins. Plus they wondered whether cultured skin cells, derived from an RBS patient, would display the same nucleolar defects like that observed earlier in a mutated baker’s yeast.

What did the scientists observe?

The scientists observed that RBS cells grew slowly. They were more likely to die than normal cells. Moreover, they exhibited aberrations directly pointing to ribosome malfunction. Most importantly, the mutant cells showed biochemical changes in cell growth pathways.  These changes included,

  • Upregulation of the activity of p53
  • Strong inhibition of mTOR

Note that p53 is a protein that senses ribosomal defects. Whereas, mTOR is a master signaling protein that encourages the production of the ribosomes, resulting in protein synthesis.

As mentioned above, the mTOR pathway can be activated with L-leucine. Thus, treatment with L-leucine remarkably rescued some RBS cell defects including protein synthesis and cell growth.

In order to observe these outcomes in a living animal, the research team analyzed zebrafish embryos carrying inactivated ESCO2. They possess several properties of human RBS like underdeveloped cranial features and slow growth. The mTOR pathways in RBS zebrafish were stimulated by supplementing them with L-leucine which resulted in better growth and development.

As per the research experts, the use of a non-toxic, inexpensive amino acid to treat human disease could be of benefit. Moreover, Leucine supplementation might improve some disease manifestations in RBS. However, many aspects of RBS are not likely to respond to post-natal leucine treatment.

This research encourages the understanding of basic biology, as it can contribute to understanding human disease.  For example, recognizing the nucleolar defect in baker’s yeast revealed the involvement of the mTOR pathway and the potential benefit of L-leucine for RBS.

The research team may look forward to extending their work and find out the potential use of Leucine treatment in other human diseases as well.



Areeba Hussain

Areeba is an independent medical and healthcare writer. For the last three years, she is writing for Tophealthjournal. Her prime areas of interest are diseases, medicine, treatments, and alternative therapies. Twitter @Areeba94789300

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