Research Location: UBC Hospital

Stroke is the fourth leading cause of death and the main source of adult disability in Canada, costing our health system $2.7 billion annually. It is caused by the interruption of flow of blood or the rupture of blood vessels in the brain, which leads to brain cell death. Depending on the area of the brain that is affected, people experience loss of different abilities including speech, movement and memory. The effects of a stroke depend on where the brain has been injured, as well as how much damage has occurred. Recovery after stroke may be related to changes in the structure and activity of brain cells. Previous studies suggested that new regions of the brain can adopt the function of damaged regions after stroke – effectively rewiring the brain for function. However, the way that brain cells change their activity after stroke, and how these changes affect recovery, is still poorly understood. Dr. Majid Mohaherani is studying the basic mechanisms that lead to the recovery of the affected area in the brain. He is examining how brain cells that survive after stroke change their activity during the weeks and months after the initial injury, rebuilding the lost connections. This research aims to provide a better understanding of the link between previously reported structural changes that occur in the brain after stroke, and changes in the activity of individual cells and large neuronal networks. This work could lead to the development of new therapeutic tools that help the brain rewire itself, which could contribute to a reduction in disabilities in stroke patients.

In the central nervous system (CNS), the chemical synapse is the major site of communication between neurons (nerve cells). There are two main types of synapses in the CNS: excitatory glutamate synapses and inhibitory gamma-aminobutyric acid (GABA) synapses. Dysfunction of GABA synapses has been identified in disorders such as autism, schizophrenia, and depression. GABA synapses are also the main targets for drugs to treat epilepsy and anxiety. The protein neuroligin is a molecule that directs a neuron to form a synapse at the place where it comes in contact with another neuron. A specific type of neuroligin, Neuroligin-2, builds GABA synapses. However, little is known about why and how Neuroligin-2 is specific for building GABA synapses. Frederick Dobie was previously funded by MSFHR for his research in protein transport in neurons. He is now studying proteins involved in synaptogenesis (the process of building a synapse). To better understand how GABA synapses are formed, he is looking at regions of Neuroligin-2 that are important for this function. He is also studying how GABA synapses can change over time, responding to the specific needs of the neuron to fit into a fully-functioning brain. He is watching the growth and maturation of synapses over a period of several days, observing in real-time the strikingly dynamic appearance, disappearance, and movement of synapses. By understanding the biology underlying GABA synapses, Dobie hopes his work will ultimately lead to the advancement of therapies for a wide range of debilitating developmental, neurological, and psychiatric disorders.

Parkinson’s disease (PD) affects 100,000 Canadians, and this number is expected to increase with the aging of the population. Primary symptoms include tremor, rigidity, slowness of movement, and posture instability. These motor disabilities are believed to be associated with the premature death of dopamine-secreting cells in the brain region Substantia Nigra pars compacta. However, the cause of this premature cell death is unknown, and symptoms often do not emerge until 80 per cent of the dopaminergic cells are lost. Detecting the onset of PD thus remains a major challenge, hindering the development of a cure. It is believed that substantial compensation occurs in the brains of PD patients, obscuring the early effects of disease. Therefore, current clinical assessments that rely on symptom severity may not provide an accurate measure of disease progression. Instead, it is predicted that abnormal brain activity changes will emerge long before substantial dopaminergic cells are lost. Thus, altered brain activity may serve as a more useful marker than symptom severity for diagnosing and treating PD. In order to disentangle compensatory mechanisms from disease effects, Bernard Ng is comparing the brain activity of PD patients at similar stages of disease progression, but with varying degrees of symptom severity. Specifically, he is using functional magnetic resonance imaging (fMRI),to study diseased-induced changes in brain activity within specific brain regions as well as changes in connectivity between brain regions. To more elaborately characterize brain activity, he is employing novel statistical spatial descriptors to examine the spatial distribution of regional activity in additional to the traditionally-employed intensity measures. By incorporating spatial information in this combined approach, better distinctions between compensatory mechanisms from disease effects would be enabled. Ng’s research aims to provide more accurate diagnosis of disease progression in PD patients, better assessment of medication effectiveness, and ultimately earlier PD detection.

Brain cells communicate with each other at junctions called synapses. Changes in synapses underlie important cognitive processes such as learning and memory. Synapse development requires communication proteins on either side of a synaptic junction. Previous research has identified genes called leucine-rich repeat transmembrane (LRRTMs) proteins, which promote formation of mammalian synapses. These novel genes are able to promote synapse formation between neighbouring cells. LRRTMs have recently been shown to be associated with neurological disorders, including schizophrenia and late-onset Alzheimer’s disease. Mutations in functionally-related proteins have also been directly been linked to autism and mental retardation. Dr. Tabrez Siddiqui is studying how synapses are formed and modified by experience. He is working to fully characterize LRRTMs in mouse models, studying the role of LRRTMs in brain morphology and synapse development. He will also identify proteins that interact with LRRTMs across the synaptic junction. A detailed study of LRRTMs and their binding partners will lead to a greater understanding of how brain cells interact with each other, and will shed light on the molecular basis of neurological disorders.

Prions are the causative agents for many brain diseases of humans and animals. In animals, the most well-known prion-related disease is bovine spongiform encephalopathy, or mad cow disease. The human prion diseases are Creutzfeldt-Jakob disease, kuru, and fatal familial insomnia. All these diseases cause brain cell death leading to difficulty walking, dementia, muscle spasms, and seizures. They are invariably fatal, and there are currently no treatments available. The incidence of human prion diseases is roughly 1 per million people per year. Unlike most other infectious diseases that are spread by bacteria or viruses, prion diseases appear to be caused by misfolded protein molecules. Protein is made of long chains of amino acids, and how a protein folds determines its function. A misfolded prion protein can interact with a normally-folded prion protein and cause it to also misfold, setting off a chain reaction that results in widespread brain cell death. How the misfolded prion causes the normal prion to misfold remains unclear. However, a new theory called the demiglobule hypothesis proposes that the misfolded prion binds to the normal prion and causes a key part of the normal protein structure, called a beta sheet, to come apart. This ultimately results in a misfolded shape. William Guest is using a variety of theoretical and experimental techniques from physics, chemistry and biology to determine whether the demiglobule hypothesis can account for prion protein misfolding. If the results of this project support the demiglobule hypothesis, researchers will know much more about how prion conversion occurs. This knowledge could ultimately enable the development of methods to block prion conversion, thereby stopping the spread of disease.

Synapses are the junctions across which signals are passed from one neuron to another. Generally, the type of input received through synapses can be classified into two categories: excitatory input increases the signal transmission, while inhibitory input reduces signal transmission. Problems that disrupt the coordination of excitatory and inhibitory inputs have been associated with the development of many severe psychiatric disorders, including schizophrenia. Recently, genetic analysis of families with a history of schizophrenia identified two genes potentially responsible for the onset of the disorder: Neuregulin1 (NRG1) and its protein receptor ErbB4. Daria Krivosheya’s recent research indicates that the ErbB4 protein receptor may help to stabilize existing synapses. Previous research has shown that ErbB4 interacts with PSD-95, a protein involved in regulating other proteins involved with excitatory synapses. Krivosheya believes interaction of the ErbB4 protein receptor with the PSD-95 protein may regulate the number of excitatory and inhibitory synapses formed by the nerve cell, while interaction with the NRG1 gene may stabilize synapses and promote branching out of dendrites, extensions of a nerve cell that conduct impulses from neighbouring cells. Krivosheya is investigating the role of NRG1-ErbB4 interaction at the synapse, as well as involvement of PSD-95 in mediating this interaction. Her goal is to explain the mechanism through which these molecules control excitatory and inhibitory synaptic balance. She hopes her research will ultimately help explain some of the physical or behavioral abnormalities associated with schizophrenia, and lead to the development of new therapies.