Increased Protein Synthesis Is a Biomarker of Fragile X Syndrome, Study Suggests

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by Alice Melão |

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Indiana University venture fund, Fragile X

Patients with fragile X syndrome have faster protein synthesis and increased protein levels than healthy people, according to a recent study. These findings suggest that protein synthesis alterations could be an important biomarker of the disease and play an important role in its development.

The study, “Protein synthesis levels are increased in a subset of individuals with Fragile X syndrome,” was published in the journal Human Molecular Genetics.

Fragile X syndrome is caused by genetic mutations affecting the FMR1 gene, and consequent loss of a functional FMRP protein. It is still unclear which biological mechanisms are altered in the absence of FMRP, but preclinical studies in mice have suggested that increased protein synthesis could be involved.

Compiled evidence suggests that therapeutic interventions on potential targets can reduce protein synthesis and enhance nerve cells’ communicative connections and plasticity, two other features affected in fragile X syndrome.

Previously, no analysis of protein synthesis had been undertaken in patients with fragile X syndrome. Now, a team of international researchers evaluated the rate of protein synthesis in fibroblasts, which are cells present in the connective tissue that produce collagen. The fibroblasts were collected from 32 patients and 17 healthy controls.

Most patients had a higher rate of protein synthesis (more than 200 percent of normal levels) when compared to controls, representing a 34 percent increase in total protein synthesis. Still, there was high variability, with about one-third of the patients showing rates within the normal range. The reported differences were not found to be correlated with patients’ age, gender, or any other technical aspect.

Interestingly, the reported changes in protein synthesis were not found to be correlated with FMR1 gene levels or its protein. This suggests that other factors may be contributing to this process in response to FMR1 deficiency.

Protein synthesis in fibroblasts and nerve cells of mice lacking the FMR1 gene was also analyzed. In these cells, the rate of protein synthesis, both in fibroblasts and nerve cells, was significantly increased, demonstrating that measures in fibroblasts predict those in neurons and can be used as a biomarker of the disease.

These data support the idea that protein synthesis is “a primary mechanism for neurodevelopmental disorders” and that this process is modulated by FMRP. However, there are likely “many other molecular factors independent of FMRP (environmental and genetic) that contribute to the modulation of homeostasis of molecules involved in synaptic plasticity,” researchers wrote.

The authors believe these findings may allow researchers to better separate fragile X patients in future clinical trials, as only a subgroup of individuals shows a net increase in protein synthesis.