Posts tagged neurodevelopmental diseases

Rett Syndrome is a neurological disorder that affects about 1 in 10,000 girls. Back in 1992, University of Edinburgh researcher Adrian Bird discovered that the protein, MeCP2, plays a major role in the disease. The story of MeCP2 is in many ways a microcosm of human genetics. It has become the showcase gene for many complex epi-genetic phenomena including X-linked inactivation, DNA methylation, and genomic imprinting. These gender-specific bargaining chips provide compatibility in an evolutionary system where sex-chromosome provisioning is inherently assymetric. In two new papers, one in Nature and the the other in Nature Neuroscience, Bird and collaborator Michael Greenberg, show how mutations found in Rett Syndrome affect the interaction of MeCP2 with a key regulatory protein known as NCoR.

Nearly all cases of Rett Syndrome are caused by mutations at various postions in the MeCP2 gene. Bird and Greenberg analyzed the locations of these mutations using the RettBase MeCp2 database, and found they cluster to two primary locations—the well-known methyl-CpG binding domain, and a new hotspot within a transcriptional repressor domain (TRD). When they compared these locations with mutations found in the general population by using the Exome Variant Server, they found no overlap. This suggests the that the MeCP2 and TRD regions are the primary regions involved in Rett’s.

The researchers hypothesized that the newly found TRD region must act through a unknown regulator of MeCP2 function. Using mass spectrometry, they were able to identify several factors which they had purified from Mecp2-EGFP “knock-in” mice. Most of these factors turned out to be subunits of the co-repressor, NCoR, which was previously known to interact with MeCP2. This is the first identified example of a protein-protein interaction known to be disrupted in Rett’s.

In the Nature paper, the researchers further report that activity-dependent phosphorylation of MeCP2 mediates its interaction with NCoR. They used a technique known as phosphotryptic mapping to identify three sites that are directly phosphorylated in MeCP2 as a result of elevation in cAMP or BDNF. More generally, they showed that membrane depolarization, and therefore activity, results in the phosporylation.

One confounding factor in trying to pinpoint the mechanisms underlying Rett Syndrome is that both loss of MeCP2, and overexpression of MeCP2, can lead to the disease. In mouse models of the disease, this could be accounted for by the observation that both loss of NCoR binding, and constitutive binding of NCoR can lead to disease symptoms. While not a complete explanation of the role of MeCP2 in the disease, it provides some clues to help dissect the involvement of the many different kinds of mutations involved.

Despite the rarity of Rett’s syndrome, its impact on our understanding of human genetics and neural development should not be underestimated. As one of the autistic spectrum disorders, research on Rett’s helps connect molecular mechanics to behavior. For example, when MeCP2 is bound to DNA it can cause condensation of the chromatin structure, and also form complexes with histone deacetylaces. In demostrating that neural activity, and subsequent signal tranduction pathways, lead to modifications of MeCP2, the researchers have revealed a path from the environment directly to the genes.

The X-linked inactivation of one copy of the MeCP2 gene in females adds another layer of complexity to the disease. The celluar mosiac formed by the pattern of inactivation, particularly in the brain, needs more study to be undersatood. The fact that Rett’s symptoms can be “rescued” in mice by the expression of MeCP2 in postmitotic neurons is encouraging. In humans, Rett’s is frequently not observed untill the first or second year of life. As MeCP2 activation correlates with this period of rapid neural maturation, Rett’s is generally considered to be neurodevelopmental disease, as opposed to a neurodegenerative disease.

Rett’s is hardly ever observed in males for the simple reason that they fail to thrive long before birth. In those rare cases that a presumably XXY male child is rescued by the additional X chromsome, as in Klinefelder’s disease, rare opportunity to study the disease etiology is afforded. The efforts of these researchers, and the larger Rett’s community, together with the insights afforded by massive data collation have turned a rare disease into a primary source of knowledge about how evolution proceeds through the interplay of the sexes at the genetic and epigenetic levels.

(Source: medicalxpress.com)

Researchers from McGill University and the University of Montreal have identified a crucial link between protein synthesis and autism spectrum disorders (ASD), which can bolster new therapeutic avenues. Regulation of protein synthesis, also termed mRNA translation, is the process by which cells manufacture proteins.
This mechanism is involved in all aspects of cell and organism function.  A new study in mice has found that abnormally high synthesis of a group of neuronal proteins called neuroligins results in symptoms similar to those diagnosed in ASD. The study also reveals that autism-like behaviors can be rectified in adult mice with compounds inhibiting protein synthesis, or with gene-therapy targeting neuroligins. Their results are published in the journal Nature.

Autism spectrum disorders (ASD) encompass a wide array of neurodevelopmental diseases that affect three areas of behaviour: social interactions, communication and repetitive interests or behaviors. According to the U.S.-based Centers for Disease Control and Prevention, 1 in 88 children suffer from ASD, and the disorder is reported to occur in all racial, ethnic, and socioeconomic groups. ASDs are almost five times more common among boys (1 in 54) than among girls (1 in 252).

“My lab is dedicated to elucidating the role of dysregulated protein synthesis in cancer etiology. However, our team was surprised to discover that similar mechanisms may be implicated in the development of ASD”, explained Prof. Nahum Sonenberg, from McGill’s Dept. of Biochemistry, Faculty of Medicine, and the Goodman Cancer Research Centre. “We used a mouse model in which a key gene controlling initiation of protein synthesis was deleted. In these mice, production of neuroligins was increased. Neuroligins are important for the formation and regulation of connections known as synapses between neuronal cells in the brain and essential for the maintenance of the balance in the transmission of information from neuron to neuron.”

“Since the discovery of neuroligin mutations in individuals with ASD in 2003, the precise molecular mechanisms implicated remain unknown,” said Christos Gkogkas, a postdoctoral fellow at McGill and lead author. “Our work is the first to link translational control of neuroligins with altered synaptic function and autism-like behaviors in mice. The key is that we achieved reversal of ASD-like symptoms in adult mice. Firstly, we used compounds, which were previously developed for cancer treatment, to reduce protein synthesis. Secondly, we used non-replicating viruses as vehicles to put a break on exaggerated synthesis of neuroligins.”

Computer modeling played an important role in this research. “By using a new sophisticated computer algorithm that we specially developed to answer Dr. Sonenberg’s questions, we identified the unique structures of mRNAs of the neuroligins that could be responsible for their specific regulation,” explained Prof. François Major, of the University of Montreal’s Institute for Research in Immunology and Cancer and Department of Computer Science.

The researchers found that dysregulated synthesis of neuroligins augments synaptic activity, resulting in an imbalance between excitation and inhibition in single brain cells, opening up exciting new avenues for research that may unlock the secrets of autism.

“The autistic behaviours in mice were prevented by selectively reducing the synthesis of one type of neuroligin and reversing the changes in synaptic excitation in cells,” explained Prof. Jean-Claude Lacaille at the University of Montreal’s Groupe de Recherche sur le Système Nerveux Central and Department of Physiology. “In short, we manipulated mechanisms in brain cells and observed how they influence the behaviour of the animal.” The researchers were also able to reverse changes in inhibition and augment autistic behaviors by manipulating a second neuroligin. “The fact that the balance can be affected suggests that there could be a potential for pharmacological intervention by targeting these mechanisms,” Lacaille concluded.

(Source: nouvelles.umontreal.ca)