In protein synthesis, within the cell cytoplasm, a succession of tRNA molecules are
matched up by base-pairing the anti-codons of the tRNA with codons of the mRNA.
Amino acids then link together extending the growing chain of proteins (black dots),
and the tRNAs, no longer carrying amino acids, are released.
This process is carried out by the ribosome, which is made up of two main chains of RNA, called ribosomal RNA (rRNA), and more than 50 different proteins.
The ribosome latches onto the end of an mRNA molecule and moves along it, capturing tRNA molecules and joining together their amino acids to form a new protein chain.
Excessive Protein Synthesis Linked to Autistic-like Behaviors
Autistic-like behaviors can be partially remedied by normalizing excessive levels of protein synthesis in the brain, a team of researchers has found in a study of laboratory mice
The findings, which appear in the latest issue of Nature, provide a pathway to the creation of pharmaceuticals aimed at treating autism spectrum disorders (ASD) that are associated with diminished social interaction skills, impaired communication ability, and repetitive behaviors.
"The creation of a drug to address ASD will be difficult, but these findings offer a potential route to get there," said Eric Klann, a professor at NYU's Center for Neural Science and the study's senior author. "We have not only confirmed a common link for several such disorders, but also have raised the exciting possibility that the behavioral afflictions of those individuals with ASD can be addressed."
The study's other co-authors included researchers from the University of California, San Francisco (UCSF) and three French institutions: Aix-Marseille Universite'; Institut National de la Santé et de la Recherche Médicale (INSERM); and Le Centre National de la Recherche Scientifique (CNRS).
The researchers focused on the EIF4E gene,
whose mutation is associated with autism.
The mutation causing autism was proposed to increase
levels of the eIF4E, the protein product of EIF4E,
and lead to exaggerated protein synthesis.
Excessive eIF4E signaling and exaggerated protein
synthesis also may play a role in a range of neurological
disorders, including fragile X syndrome (FXS).
In their experiments, the researchers examined
mice with increased levels of eIF4E.
They found that these mice had exaggerated levels of
protein synthesis in the brain and exhibited behaviors
similar to those found in autistic individuals,
repetitive behaviors, such as repeatedly burying marbles,
diminished social interaction (monitored interactions
between mice), and behavioral inflexibility (the afflicted
mice were unable to navigate mazes that had been
slightly altered from ones the mice had previously solved).
The researchers also found altered communication between neurons in brain regions linked to the abnormal behaviors.
To remedy to these autistic-like behaviors, the researchers then tested a drug, 4EGI-1, which diminishes protein synthesis induced by the increased levels of eIF4E. Through this drug, they hypothesized that they could return the afflicted mice's protein production to normal levels, and, with it, reverse autistic-like behaviors.
Subsequent experiments confirmed their hypotheses.
The mice were less likely to engage in repetitive
behaviors, more likely to interact with other mice,
and were successful in navigating mazes that differed
from those they previously solved, thereby showing enhanced behavioral flexibility.
Additional investigation revealed that these changes
were likely due to a reduction in protein production,
the levels of newly synthesized proteins in the brains
of these mice were similar to those of normal mice.
"These findings highlight an invaluable mouse model for autism in which many drugs that target eIF4E can be tested," added co-author Davide Ruggero, an associate professor at UCSF's School of Medicine and Department of Urology. "These include novel compounds that we are developing to target eIF4E hyperactivation in cancer that may also be potentially therapeutic for autistic patients."
The study's other co-authors were: Emanuela Santini, the study's lead author, Thu Huynh, Andrew MacAskill, Adam Carter, and Hanoch Kaphzan of NYU's Center for Neural Science; and Philippe Pierre of Aix-Marseille Université, INSERM, and CNRS.
The research was supported by grants from the National Institutes of Health (NS034007, NS047384, NS078718, and CA154916), a Department of Defense Congressionally Directed Medical Research Program award (W81XWH-11-1-0389), and the Wellcome Trust.
Original article: http://www.eurekalert.org/pub_releases/2012-12/nyu-nfe122012.php