Severe psychiatric disorders affect three to five per cent of Canadians. One of these diseases is called Bipolar Affective Disorder Type I (BPDI). People with this disorder manifest many unusual manic behaviours. They typically do not sleep much, feel like they are on top of the world, have racing thoughts and are easily distracted. However, most BPDI patients also have depressive episodes and 15 per cent will commit suicide. The recurrence rate for BPDI is 90 per cent, making it a life-long disorder. Unfortunately, it is incurable and difficult to manage with current therapeutics. The brain transcription factor Nr2e1 controls the proliferation and differentiation of neural stem cells, which are required for the formation of neurons (neurogenesis). Some people with BPDI show dysplasia of forebrain and neurogenic regions and treatment that improve symptoms of bipolar disorder are known to stimulate neurogenesis. Mice that have a non-functional version of the Nr2e1 gene (dubbed ’fierce’ mice) display similar severe mania-like behaviour and defects in neurogenesis as observed in people with BPDI. Charles de Leeuw is investigating the use of MiniPromoters – DNA constructed from small conserved regions of a gene that tell it when and where it should turn on – to affect gene expression in specific brain regions of fierce mice. He will use the MiniPromoters to deliver Nr2e1 to the neural stem cells that are defective but also in the neurons that are generated from defective stem cells, both types of cells which are involved in the fierce mice defects. If he is able to prompt the gene to be turned on in the correct area of the brain, de Leeuw anticipates he will be able to ‘cure’ some of the mania-like behaviours in mice. His goal is to determine the potential for treating the genetic cause of BPDI through the use of MiniPromoters and human NR2E1. His experiments will also help shed light on the neurodevelopmental causes of manic behaviour.
Research Location: CMMT
Chromatin mishandling in Huntington disease: potential links to pathogenesis and points of therapeutic intervention
Huntington disease (HD) is a hereditary neurodegenerative disorder that affects 3,000 Canadians. Patients with a HD mutation experience adult-onset psychiatric symptoms, cognitive impairment and motor disturbances that progressively worsen over many years and lead to death. Despite a massive world-wide research effort, there is still no means of prevention, no treatment, and no cure for HD. Recent studies confirm that psychiatric and cognitive changes occur in at-risk individuals several years before formal HD diagnosis. The ability to understand and reverse these early cognitive changes may lead to a cure for HD. Chromatin is the genomic DNA-protein complex that specifies how to make proteins and when and where to do so. Recent studies show that the way genetic material is packaged into chromatin in brain cells can be altered by early life experiences (such as learning), and can affect behaviour. Alterations in chromatin regulation have been observed in depression, bipolar disorder and schizophrenia. Many effective psychiatric drugs have been found to influence chromatin regulation. Mendel Grant is examining a possible link between chromatin and the onset and progression of HD. She is testing her hypothesis that environmentally-responsive chromatin changes (such as those induced by learning) do not function normally in a mouse model of HD. This could underlie cognitive dysfunction observed in HD patients and animal models. If chromatin is shown to be misregulated in HD, the use of FDA-approved neuropsychiatric drugs that alter chromatin regulation could be a promising therapy. Information yielded from this study may also be applicable to other neurodegenerative disorders including Alzheimer and Parkinson diseases and psychiatric conditions such as depression.
The role of ABC transporters on cellular cholesterol homeostasis and beta-cell function
Type 2 diabetes affects more than two million Canadians and causes a range of significant health issues, including coronary heart disease, the leading cause of death in Canada. Type 2 diabetes results from a relative insufficiency of beta-cells in the pancreas to produce enough insulin to meet the increasing metabolic demands caused by obesity and aging. Cholesterol levels among type 2 diabetes patients is also known to commonly be altered, with elevated levels of LDL (“bad cholesterol”) and low levels of HDL (“good cholesterol”). However, the mechanistic connections between cholesterol metabolism and diabetes are poorly understood. Researchers recently discovered that the cholesterol transporter ABCA1, which is crucial for regulating cholesterol levels inside cells, is also essential for the normal release of insulin in beta-cells. Mice that lack Abca1 in their beta-cells have impaired glucose tolerance due to impaired beta-cell function. Dr. Janine Kruit is working to determine the specific role of ABC transporters in beta-cell function, glucose metabolism and type 2 diabetes. Her research will focus on the cholesterol transporters ABCA1 and ABCG1. Her studies could suggest a novel mechanism for how type 2 diabetes develops, and lead to new ways to prevent and treat this disease.
To define the role of caspases and caspase cleavage of htt in the pathogenesis of HD
Research has identified a genetic defect in the HD gene that causes Huntington’s disease, a devastating and ultimately fatal neuropsychiatric disease. Symptoms include progressive deterioration in the ability to control movements and emotions, recall recent events or make decisions, and leads to death 15 to 20 years after onset. One in 10,000 Canadians has HD. There is neither a cure nor treatments to prevent Huntington disease. Several years ago Dr. Hayden and his team discovered that huntingtin, the protein involved in Huntington disease (HD), is cleaved by ‘molecular scissors’ which are proteins called caspases. This discovery led to the hypothesis that cleavage of huntingtin may play a key role in causing HD. To explore the role of huntingtin cleavage in the disease process, we established an animal model of HD that replicated the key disease features seen in patients. A unique aspect of this particular animal model is that it embodied the human HD gene in exactly the same way seen in patients. This replication allowed researchers to examine the progression of HD symptoms including the inevitable cleavage of the mutant huntingtin protein. Dr. Rona Graham is continuing her earlier MSFHR-funded research into understanding the reason why the mutant form of the HD gene causes death of particular neurons in the brain. Her Masters and PhD work demonstrated that preventing cleavage of the mutant huntingtin protein responsible for HD in a mouse model, the degenerative symptoms underlying the illness do not appear and the mouse displays normal brain function. Dr. Graham’s goal now is to investigate the role of caspase activation and the caspase-6 cleaved huntingtin fragment in the disease process. Since a similar splitting of disease proteins is involved in many other central nervous system diseases including Alzheimer’s and Spinocerebellar ataxia (which causes progressive deterioration in hand, speech and eye movement) Dr. Graham hopes the findings will lead to new treatments for other neurological disorders as well as HD.
Role of ABCA1 in brain cholesterol metabolism and brain function
Although the brain accounts for only 2 per cent of total body weight, it contains almost 25 per cent of total body cholesterol. This cholesterol is critical to healthy functioning in the brain, and plays an important role in learning. Abnormalities in the synthesis of brain cholesterol are associated with several devastating diseases, including Alzheimer’s and Huntington’s. However, not much is known about how the central nervous system regulates the metabolism and movement of cholesterol in the brain. Two-thirds of brain cholesterol is located in myelin, an insulating layer that surrounds the nerve fibers of brain cells where it supports transmission of signals between neurons across connections called synapses. Cholesterol also helps repair neurons. Although the synthesis of cholesterol occurs at a high level in the developing brain, it declines significantly in the adult brain. Consequently, the brain must rely on efficient transport and recycling to meet its need for cholesterol in the brain cells. Dr. Joanna Karasinska is investigating whether ABCA1, a major cholesterol transporter in the brain, controls the metabolism of cholesterol and how this affects brain function. This knowledge could lead to new therapies for neurological disorders associated with a cholesterol imbalance in the brain, and for the repair of neurons following a brain injury.
Modulating proteolysis in Huntington disease: Eluding the toxic fragment
Huntington’s disease is an inherited neurodegenerative disorder primarily caused by the early death of brain cells. The disease typically begins with mental and emotional disturbances, which progress to involuntary, jerky movements. An abnormal form of the Huntingtin protein is associated with Huntington’s disease. Huntingtin is made of 3144 amino acids, or molecular building blocks. In a landmark study, after mutating just one of those building blocks, genetically modified caspase-resistant mice (those resistant to intracellular proteins that lead to cell disintegration) were completely protected from all symptoms of Huntington’s disease. Jeffrey Carroll’s research aims to find medical interventions beyond genetic modification that produce the same effect. He is developing tools to quickly analyze the effectiveness of drugs at inhibiting cell disintegration. He has designed and is building a cell-based system that allows him to screen libraries of hundreds of thousands of drugs that might offer some protection. Carroll is also investigating a protein-cutting enzyme, caspase-2, who’s activity is dramatically reduced in caspase-resistant mice. Carroll aims to increase understanding of the pathway between Huntingtin and caspase-2. Findings could contribute to therapies for Huntington’s disease.
Genetic discrimination in mutation carriers identified through predictive testing for HD
In her earlier research supported by a MSFHR-BCMSF Junior Graduate Studentship Trainee Award, Yvonne Bombard completed a qualitative study of how individuals live with, and manage the potential for, genetic discrimination. Based on these findings, she adapted an Australian survey to reflect the concerns and experiences relevant to Canadians at risk for Huntington’s disease (HD). Yvonne’s work now focuses on recruiting 300 Canadian participants to complete the adapted survey. Survey results will then be analyzed to identify the nature and frequency of discrimination against Canadians who test positive for the HD gene mutation (but who have not yet developed outward symptoms) when applying for insurance, in their work environment, and in social and family settings. The findings of the study will help counsellors, patient support groups, and the health policy communities identify areas where more education or policy may be needed. Ultimately, this research may lead to better supports and improved health of individuals identified as being at risk for developing Huntington’s disease.
The contribution of hepatic ABCA1 to HDL levels and composition, and suceptibility to atherosclerosis
Coronary artery disease is a leading cause of death among Canadians. High cholesterol has been identified as a major risk factor for the disease. However, there are two kinds of cholesterol: LDL, the so-called “bad” cholesterol that has been linked to coronary artery disease, and HDL, the so-called “good” cholesterol that has been linked to lower incidence of heart disease. Currently, the medical community’s focus is on decreasing LDL levels, but more than fifty percent of people with premature coronary artery disease have low levels of HDL. A gene called ABCA1 has been identified as critical in the production of HDL, but there is still uncertainty about its function. ABCA1 exists in most tissues of the body, but some tissues – notably the liver – are particularly rich in it. Liam Brunham is investigating the role of ABCA1 in the liver and in the production of HDL. Learning about this gene will increase understanding of how the human body produces and uses cholesterol and how it responds to different diets.