A Brief Description of Currently Funded Research Grants 2013 – 2014
The Role of DSCAM in Neural Development
Dr. Brian Chen
Research Institute of the McGill University Health Centre
Department of Neurology, Montreal General Hospital
Chromatin modifiers in neurodevelopmental disorders
Dr. Carl Ernst
Douglas Hospital Research Centre
Introduction: Fifteen to twenty percent of all cases of neurodevelopmental disorders (NDDs) are associated with a known genetic mutation, yet these mutations are individually rare, usually occurring in only a small proportion of subjects. Some genes that are mutated in people with NDDs are master regulators of the cell, meaning they turn many other genes on or off. Some of these mutated genes may have overlapping targets and these overlapping targets might define a common molecular pathway(s) for people with NDDs. In other words, NDDs may be caused not by the mutation in a particular gene itself, but because of the effects a mutated gene has on turning other genes on or off; if mutated genes associated with NDDs turn the same genes on and off, or a proportion of them, this might suggest a common molecular pathway of NDDs.
Investigating a Wnt/GSK3 signaling network in Autism spectrum disorders and novel therapeutic interventions
Dr. Karun Singh
Purpose of the Research: Autism spectrum disorders (ASDs) are neurodevelopmental disorders in which individuals have disrupted social communication and repetitive stereotyped behaviors, which lead to life-long difficulties. Approximately 1 in 88 individuals in North America have an ASD, which demonstrate the need to better understand these disorders, and find effective treatments to improve quality of life. In this regard, recent studies have identified over 2000 genes that are risk factors for ASDs. Given this large information, it is very difficult to determine which genes are the most important and should be the focus of further investigation and drug development. Many labs have attempted to simplify thisinformation by finding “hubs”, called common signaling pathways, which converge the actions of multiple genetic risk factors. The discovery of signaling hubs would makes it possible to develop drugs that target it specifically instead of the many individuals genes that contribute to ASD. In the current proposal, we will study a new “hub” named Wnt/GSK3 signaling in animal models. Our goal is to test whether multiple ASD-linked genes converge and disrupt Wnt/GSK3 signaling, and contribute to the risk of ASDs by causing abnormal fetal brain development. Finally, we will test the exciting possibility that drugs used to treat high cholesterol, which are safe for use in humans, could be used to correct abnormalities in the Wnt/GSK3 hub, and be developed as new ASD therapeutics.
Proposed Research Plan: Aim 1. We will determine whether 3 specific ASD-linked genes (FMRP, DISC1 and CHD8) converge to regulate Wnt/GSK3 signaling. We will accomplish this by altering the amounts of FMR1, DISC1 or CHD8 proteins in mouse brain stem cells, followed by use of a fluorescent indicator to measure changes in Wnt/GSK3 signaling.
Aim 2. We will determine whether the FMRP/DISC1/CHD8 signaling network impacts the growth of
developing mouse brain stem cells, since this may be disrupted in individuals with ASD.
Aim 3. Lastly, we will attempt to correct the reduction in Wnt signaling that we believe is driving many of developmental brain defects in ASDs. We will accomplish this by testing FDA-approved cholesterol reducing drugs in mice for their ability to stimulate the activity of Wnt/GSK3 signaling and correct brain stem cell growth.
Anticipated Outcome: We predict the FMRP/DISC1/CHD8 gene network will be a critical regulator of the Wnt/GSK3 signaling hub. Furthermore, our studies will reveal that inhibiting the FMRP/DISC1/CHD8 network will cause abnormalities in the growth and behavior of mouse brain neural stem cells, which will cause defects in brain development and risk for ASDs. Finally, we anticipate FDA-approved cholesterol lowering drugs will reverse these effects by stimulating Wnt/GSK3 signaling and restoring normal mouse brain stem cell development.
Project Benefits and Applications of Findings: Our proposed studies will have a number of benefits for ASDs. First, our experiments will uncover a new and important autism signaling “hub” that converges the actions of multiple ASD-linked genes, and will provide greater insight into the causes of ASDs. Most important, identifying the Wnt/GSK3 signaling hub will provide a new target to develop drugs. To this end, our initial studies will repurpose FDA-approved cholesterol-reducing drugs to correct abnormalities in the hub’s activity within brain stem cells of animal models, as a potential novel therapy for ASDs. Since our studies will reveal how cholesterol-reducing drugs produce their beneficial effects in brain cells, this will give us the opportunity to minimize their side-effects and improve safety in future studies. Lastly, because the statin drugs are well characterized in humans, and have low toxicity, we can rapidly move into ASD clinical trials if our animal model studies reveal they stimulate the Wnt/GSK3 hub and restore normal brain development.
The roles of microglia-synapse interactions in Alzheimer’s disease
Dr. Marie-Eve Tremblay
CHU de Québec
1) Measure the prevalence of microglial contacts (both phagocytic and non-phagocytic) with dendritic spines and axon terminals.
2) Categorize the contacted synaptic elements into particular subsets based on their healthy, stressed (but viable) or degenerating nature, considering that phagocytosis of such elements could serve distinct roles. Primary phagocytosis of viable neurons and synapses could induce neurodegeneration in AD by causing cell death, while secondary phagocytosis, or clearance of degenerating neurons and synapses following their death, could have beneficial effects on the maintenance of neuronal circuits.
3) Measure the formation and elimination rates of these contacted elements (healthy, stressed or
degenerating) with relation to amyloid-β plaques deposition.
a) Basic insights into the possible roles of microglia-synapse interactions in AD;
b) Better understanding of the mechanisms by which phagocytosis-promoting treatments ameliorate learning and memory –irrespective of microglial intervention;
c) Novel reference measurements to help evaluating additional treatments in clinical development for AD with respect to their consequences on synapses and neuronal circuits.
Such insights will contribute to enrich, orient and refine current working hypotheses on the complex pathogenesis of AD by including the brain immune cells as a novel, potentially important player.