Research Projects

The Challenge: The prevalence of age-related neurodegenerative disorders is increasing dramatically as people live longer and now affects millions of people worldwide. Indeed, the single greatest risk factor for Alzheimer disease (AD) is age. Due to this sharp increase, the total costs associated with dementia over the next 30 year is predicted to cost $870 billion in Canada alone. Furthermore, in Canada, the US and Europe, stroke is the leading cause of long term adult disability and the 3^rd leading cause of death (2^nd leading cause of death world wide). The economic burden due to stroke related illness alone is estimated to be 3.6 billion/year in Canada. Studies in AD, Huntington disease (HD) and stroke suggest similarities in the underlying molecular mechanisms and indicate that studies on HD could shed light on critical pathways affected in AD and stroke.

At the present time there are no effective therapies, and there is a lack of affordable, expeditive biomarkers to predict and/or monitor disease progression. Furthermore, it is becoming increasingly evident that physicians need practical clinical tools that integrate knowledge across multiple domains of function in order to make evidence based personal decisions for their patients. Olfactory dysfunction and altered neurogenesis are observed in several neurological disorders including Alzheimer, Parkinson and Huntington disease. These deficits occur early in the phenotype and correlate with global cognitive performance, depression and degeneration of olfactory regions in the brain. These data suggest that olfactory dysfunction is a potential biomarker of future cognitive impairment and may be useful as an endpoint in clinical or murine neurodegenerative therapeutic trials. The overall goal of our research is to establish if olfactory dysfunction accurately predicts impending cognitive decline in humans and to determine the underlying mechanism(s) responsible in order to define novel therapeutic approaches for neurodegenerative diseases. Identification of biomarkers will contribute substantially to our understanding of the pathogenesis of the disease and brain-behaviour relationships, and enable assessment of the efficacy of putative therapies. The end result will be integration of knowledge generated into clinical practice.

The involvement of apoptotic cell death in neurodegeneration has been shown for several disorders, including HD, AD and cerebral ischemia. Each of these diseases is associated with excitotoxicity, activation of caspases and significant cell loss. Caspases modify their substrates through cleavage at specific recognition sites and cause either inactivation of the protein or a gain of function through generation of active proteolytic fragments. Caspase-6 in particular has emerged as an important player in the neuronal degeneration and death in HD, AD and stroke. Casp6 has been shown to function as an initiator caspase through its ability to cleave and activate other caspases and activation of casp6 is observed prior to the clinical and pathological diagnosis of both HD and AD. This includes an important role for casp6 in axonal degeneration, which makes a profound contribution to neuronal loss in neurodegenerative disorders. Importantly, preventing the proteolytic processing of mutant huntingtin and/or amyloid precursor protein or by casp6 in the case of HD and AD respectively, or targeted deletion of casp6 has been beneficial in these conditions

DEFINITIONS OF KEY TERMS

Apoptosis: Programmed cell death or apoptosis is a program found within in all cells that once triggered leads to activation of caspases, cleavage of specific proteins and eventual death of the injured cell.

Caspases: Caspases cleave with remarkable specificity at recognition motifs present in a discrete and limited subset of cellular polypeptides (substrates). This cleavage event results in inactivation of the protein or in generation of fragments with novel functions compared to the parent protein.

Excitotoxicity: This is a pathological process that involves dysfunction of glutamate receptors, in particular N-Methyl-D-aspartic acid (NMDA) receptors. Excitotoxins bind to these receptors and can cause excitotoxic stress due to high levels of calcium ions entering the cell, protease activation and eventual cell death. Excitotoxic neuropathological changes are observed in AD, HD and stroke and are considered to be an early event in the pathogenesis of these diseases.

Interactome/interactors: An interactome refers to the physical protein-protein interactions in cells. As an example, the caspase-6 (casp6) interactome is composed of all the proteins that physically interact (interactors) with casp6.

Neurodegenerative diseases: Neurodegeneration, the loss of structure and function of neurons in the brain, causes cellular dysfunction leading to cognitive deficits and the eventual death of brain cells. Several neurodegenerative or neurological diseases, including AD, HD and stroke, occur as a result of a neurodegenerative process.

Stroke: Rapid loss of brain function caused by a loss of blood flow to the brain. Most strokes are caused by a blood clot in the brain (ischemic stroke or brain ischemia). Middle cerebral artery occlusion (MCAO) is a common technique to induce stroke in animal models

Yeast-2-hybrid (Y2H): In order to gain a deeper understanding of the molecular function of a protein, a key technique used in molecular biology is to determine with what proteins it interacts with. Y2H screening is one such technique employed to discover protein interactions. As Y2H screening, and other such high-throughput techniques, can result in false negative (and false positive) identifications, validation is critical to provide convincing evidence of the interaction.