Journey to the end of the neuron

Edouard Khandjian

Edouard Khandjian

Study confirms the existence of a molecular transport mechanism involved in fragile X syndrome

A team from the Centre de recherche de l’Institut universitaire en santé mentale de QuébecUniversité Laval has furthered our understanding of fragile X syndrome, the leading genetic cause of mental retardation in children. The article published by these researchers in a recent issue of PLoS Genetics confirms the model developed over 14 years by the team of Professor Edward Khandjian, and reveals new elements.

Fragile X syndrome is a disease that affects one boy in 4000 and one girl in 7 000. Its symptoms include learning difficulties, language disorders and hyperactive or autistic behaviors. This syndrome is caused by the absence of FMRP (Fragile X Mental Retardation Protein), due to mutations in the FMR1 gene on the X chromosome. FMRP protein is present in all body tissues, but its concentration is 100 times higher in nerve cells. Its absence is therefore particularly felt where it is normally abundant, which would explain the development of cognitive problems in individuals with fragile X syndrome. “In the brain, FMRP is involved in the development of neurons, their maturation and the formation of neural circuits,” says Professor Khandjian.

The work carried out since 2002 by his team suggests that FMRP plays an important role in the transport of messenger RNA (mRNA) from the nucleus of the neuron, where they are synthesized, to remote sites, where they are translated into proteins. “In humans, this distance can reach up to a meter”, says Khandjian. “FMRP binds to mRNA, forming RNA granules, and keeps them silent until the granules are delivered, by way of microtubules, in the region of the cell where protein synthesis is occurring, e.g. the synapse. If there is a deficiency of FMRP, the pellets are not transported or incompletely transported, preventing the normal production of proteins involved in the formation of dendritic spines and therefore of neural plasticity. ” To illustrate this mechanism, the researcher has a railway analogy. “Microtubules are as rails on which run the wagons (granules) containing the genetic information (mRNA) to remote plants (polyribosomes), specialized in the synthesis of proteins involved in neuronal plasticity.”

To determine if this model was accurate, the researchers labeled FMRP with a fluorescent protein and they filmed its movements inside living neurons by using fluorescence microscopy. The images obtained confirmed their model and added unexpected elements. “We found that some of the granules also contains polyribosomes. These granules therefore carry with them not only silenced FMRP mRNA, but also the factory which will be used to convert them into proteins, “said Professor Khandjian. The images also reveal that the granules merge during their journey on microtubules. “It is possible that this mechanism of “mass transit “serves to minimize energy expenditure in the cell, he proposes. These freighters disassemble when they reach their destination. ”

These advances in our understanding of fragile X syndrome will not lead to a short-term treatment, warns Professor Khandjian, but they open new venues of investigation. The molecules tested in clinical trials on humans have led to dead ends, he recalls, because we burned the steps. “You have to understand the fundamental mechanisms involved in this disease before you can hope to find a solution. The study of the granules may be applied to other pathologies involving proteins binding mRNA, such as amyotrophic lateral sclerosis and spinal muscular atrophy. ”

The study was published in PLoS Genetics and is authored by Rachid El Fatimy, Sandra Tremblay, Alain Dury, Paul De Koninck and Edward Khandjian, at the IUSMQ – Université Laval, Claude Robert, Biology Research Center of reproduction, Laetitia Davidovic of the University of Nice-Sophia Antipolis, and Xavier Jaglin, of New York University.


Source of text: Le Fil de l’Université Laval (includes pictures and videos of the RNA granules.)

Translation : CAN-ACN

Original research article :

El Fatimy R, Davidovic L, Tremblay S, Jaglin X, Dury A, Robert C, De Koninck P, Khandjian EW. Tracking the Fragile X Mental Retardation Protein in a Highly Ordered Neuronal RiboNucleoParticles Population: A Link between Stalled Polyribosomes and RNA Granules. PLoS Genet. 2016 Jul 27;12(7):e1006192. doi: 10.1371/journal.pgen.1006192. eCollection 2016 Jul.