Michael Hayden


Research Interests

Disease progression
Drug development
Gene Therapy
Genetic Diseases
Huntington disease
Neurodegenerative diseases
Neurodegenerative disorders

Relevant Thesis-Based Degree Programs



Dr. Michael Hayden is a Killam Professor at the University of British Columbia (UBC) and holds the Canada Research Chair in Human Genetics and Molecular Medicine. He is a Senior Scientist at the Center for Molecular Medicine and Therapeutics (CMMT) in Vancouver, Canada; a genetic research center within UBC. He is also the Program Director of the Translational Laboratory in Genetic Medicine in Singapore, and was appointed in 2012 as the President of Global R&D and Chief Scientific Officer at Teva Pharmaceutical Industries.

Dr. Hayden was recently named one of the 50 Canadians born in the 20th century who have changed the world. Dr. Hayden is the co-founder of five biotechnology companies: Prilenia, NeuroVir Therapeutics Inc., Xenon Pharmaceuticals Inc., Aspreva Pharmaceuticals Corp, and 89bio. Dr. Hayden currently sits on different public and private boards of biotechnologies companies..

Author of approximately 900 peer-reviewed publications and invited submissions (h-index 142 Google Scholar; 117 Web of Science), Michael has focused his research primarily on genetic diseases, including genetics of diabetes, lipoprotein disorders, Huntington disease, predictive and personalized medicine. Michael and his research group have identified 10 disease-causing genes which includes the identification of the major gene underlying high-density lipoprotein (HDL) in humans. This gene, known as ABCA1, has major implications for atherosclerosis and diabetes. Michael also identified the first mutations underlying Lipoprotein Lipase (LPL) Deficiency and developed gene therapy approaches to treat this condition, resulting in the first approval of gene therapy in the world in 2012 (Glybera). He is the most cited author in the world for ABCA1 and Huntington Disease.

Michael is the recipient of numerous prestigious honours and awards. He was recently inducted into the Canadian Medical Hall of Fame (2017). He was named one of PharmaVoice’s “100 of the Most Inspiring People” (2015); awarded an Honorary Doctor of Science by the University of Gottingen (2014); awarded the Luminary award by the Personalized Medicine World Conference (2014); awarded the Diamond Jubilee Medal, on behalf of HRH Queen Elisabeth II (2012), in recognition of his significant contributions and achievements; received the Margolese National Brain Disorder Prize (2011), awarded to Canadians who have made outstanding contributions to the treatment, amelioration, or cure of brain diseases; awarded the Killam Prize by the Canada Council of the Arts (2011), in recognition of his outstanding career achievements; and the Canada Gairdner Wightman award (2011), recognizing him as a physician-scientist who has demonstrated outstanding leadership in medicine and medical science. Michael has also been awarded the Order of Canada (2011), and the Order of British Columbia (2010). He was named Canada’s Health Researcher of the Year by CIHR (NIH of Canada) in 2008, and he received the Prix Galien in 2007, which recognizes the outstanding contribution of a researcher to Canadian pharmaceutical research.

Michael is committed to empowering others. In addition to mentoring over 100 graduate students and postdocs, he is also a TED mentor. Michael has initiated and leads an international effort to bring benefit to a community living with HIV/AIDS in South Africa. In collaboration with colleagues around the world, he spearheaded and built a youth-friendly recreation, counseling, and Learning Centre in direct partnership with the township of Masiphumelele in Cape Town.


Postdoctoral Fellows
Any time / year round

Hayden Lab Research Projects

Huntington Disease (HD) is a devastating incurable neurodegenerative disease that affects about 5,000 Canadians. Inheriting a single mutant copy of the Huntingtin (HTT) gene from either parent is sufficient to cause HD. The mutated HTT gene codes for production of the toxic, mutant huntingtin protein (mHTT) that is responsible for killing brain cells in HD. Importantly, the other, non-mutated (or normal) copy of the huntingtin protein is critical for the health of brain cells. Consequently, our research goals are to reduce mHTT through multipronged approaches that specifically target the mutant gene and also develop approaches to enhance the clearance of mutant protein.

The ultimate goal of my research is to develop new therapies that slow down or reverse progression of HD and lead to preventative therapy for pre-symptomatic individuals.

My current research projects include:

Silencing the gene that causes Huntington disease– Mutant huntingtin protein is the cause of Huntington disease (HD) and engages in a variety of aberrant interactions in neurons. Preventing generation of this toxic protein by gene silencing, the process of switching off a gene, should prevent all subsequent pathology and prevent or delay the onset of HD. Everyone has two copies of the huntingtin gene. In HD, one of these copies carries the mutation while the other copy is normal. The normal huntingtin protein is important for maintaining neuronal health and long-term reduction of this protein may not be well-tolerated. We are developing a strategy of silencing only the mutant copy of a patient’s huntingtin gene using antisense oligonucleotides targeted to HD mutation-associated single nucleotide variants as a treatment for HD.

Modulating mHTT post-translational modifications (PTMs) to enhance its clearance – Huntingtin (HTT) undergoes a myriad of post-translational modifications (PTMs) including phosphorylation, proteolytic cleavages and fatty acylation that influence the protein function, localization and clearance. Those PTMs are essential for neuronal viability, but are altered in HD. We have shown that promoting or preventing specific HTT PTMs can either dramatically improve or exacerbate HD symptoms. There is also evidence that HTT PTMs work in concert and may regulate one another. However, the interactions between the networks of HTT PTMs remain mostly unstudied. Our objectives are therefore to identify new rate-limiting PTMs, characterize the interrelationship of the HTT PTM network in vivo and understand how it relates to HTT function, stability and clearance. This project will allow us to determine and validate molecular targets for therapeutic strategies that could be used in synergy with HTT gene silencing.

Discovery of novel therapeutic targets for neuroprotection in Huntington Disease – Glutamate excitotoxicity and mitochondrial dysfunction are critical, closely-linked pathogenic mechanisms in several acute and neurodegenerative brain disorders, including HD. Together, these processes contribute to altered intracellular calcium dynamics, bioenergetic defects, cell death signaling, and synaptic instability. We are investigating novel therapeutic targets involved in these pathways with the goal of improving mitochondrial health and normalizing synaptic function in HD.

Population genetics and epidemiology of the Huntington disease mutation – The HD mutation is associated with specific sets of genetic variants in the surrounding HTT gene, known as haplotypes. We are performing detailed investigations of haplotypes HD mutation in different populations around the world. Haplotypes of the HD mutation allow for identification of new targets for therapeutic gene silencing and offer insight into the origin of the HD mutation in different ethnic groups. We additionally study how many people have the HD mutation, how often this mutation results in HD symptoms, and how often unstable new mutations for HD occur in the general population.

Redevelopment and optimization of an adeno-associated virus gene therapy product for the treatment of lipoprotein lipase – We developed, Glybera, a gene therapy-based treatment for LPLD. Glybera became the first gene therapy-based treatment in the world that received regulatory approval in 2012. However, due to its extremely high price, it is no longer marketed. In collaboration with the National Research Council of Canada, we are currently working on a project to develop a novel, more efficacious, and cost-effective gene therapy treatment for LPLD. Our lab has won several prestigious awards to support this work, including the CIHR Postdoctoral Fellowship and the MFSHR Research Trainee Award. These competitive awards provide tremendous opportunities and enable our lab to fully engage in this critical work, which will directly benefit patients.

I support public scholarship, e.g. through the Public Scholars Initiative, and am available to supervise students and Postdocs interested in collaborating with external partners as part of their research.
I support experiential learning experiences, such as internships and work placements, for my graduate students and Postdocs.
I am open to hosting Visiting International Research Students (non-degree, up to 12 months).

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Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Understanding and modulating synaptic dysfunction in Huntington disease (2019)

Huntington disease (HD) is a devastating neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Early disrupted cortico-striatal (CS) transmission contributes to neuronal spine and synapse dysfunction primarily in striatal medium spiny neurons (MSNs), the most vulnerable cell type in HD, as well as in cortical neurons. Irreversible neurodegeneration of MSNs occurs with disease progression, leading to motor, cognitive, and psychiatric symptoms. However, synaptic dysfunction and spine loss are hypothesized to be therapeutically reversible before neuronal death occurs. One of the earliest alterations to occur in HD mouse models is enhanced striatal extrasynaptic (ex) N-methyl-D-aspartate receptor (NMDAR) expression and activity. This activity is mediated primarily through GluN2B subunit-containing receptors and is linked to increased activation of cell death pathways, inhibition of survival signaling, and greater susceptibility to excitotoxicity. Death-associated protein kinase 1 (DAPK1) is a pro-apoptotic kinase highly expressed in neurons during development. DAPK1 becomes re-activated and recruited to exNMDARs during ischemia where it phosphorylates GluN2B at S1303, amplifying receptor function. Approaches to reduce DAPK1 activity have demonstrated benefit in animal models of stroke, Alzheimer disease, Parkinson disease, and chronic stress, indicating that DAPK1 may be a novel target for neuroprotection. The overall hypothesis of this thesis was that aberrant DAPK1 activity contributes to exGluN2B dysfunction in HD, leading to early CS synaptic instability. An in vitro CS co-culture model was extensively optimized to allow rapid and robust detection of HD-like CS synaptic phenotypes, including MSN spine loss. Early dysregulation of DAPK1 was observed in the YAC128 HD mouse model, which was associated with elevated exGluN2B pS1303. Inhibition of DAPK1 normalized exGluN2B phosphorylation and surface expression, and completely prevented YAC128 MSN spine loss in CS co-culture. DAPK1 silencing restored nuclear CREB activation and partially rescued age-associated dendritic spine loss in vivo, thus validating DAPK1 as a target for synaptic protection in HD and warranting development of DAPK1-targeted therapies for neurodegeneration.

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Population genetics and allele-specific silencing of the Huntington disease mutation (2017)

Huntington disease (HD) is a devastating neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin gene (HTT). A repeat of ≥36 CAG defines the HD mutation and is diagnostic in the presence of motor or psychiatric phenotypes. All patients have an expanded CAG repeat, usually inherited from an affected parent and heterozygous with a normal (≤35) CAG repeat allele. This thesis addresses numerous gaps in our understanding of the HD mutation at the population level, including heterozygote frequency, penetrance, ancestry, the de novo mutation rate, and haplotypes useful for therapeutic gene silencing. Dense SNP genotyping across HTT in HD patients and relatives from Canada, Sweden, France, and Italy allowed definition of the three most common HD mutation haplotypes in populations of European ancestry. All common defining alleles of these haplotypes were identified from the 1000 Genomes Project reference data and validated by direct genotyping of HD patients and their families. Haplotypes of the HD mutation provide mutually exclusive sets of target variants for allele-specific HTT silencing in the maximum number of European ancestry patients. Haplotypes of the HD mutation were investigated in additional HD patient populations worldwide. The HD mutation in Peru occurs most frequently on the A1 HTT haplotype, as in Europe, but on a distinct A1 variant found in Amerindian controls, supporting an indigenous origin of the HD mutation in Latin America. The general population frequency of the HD mutation was estimated from CAG repeat genotyping of 7315 individuals in Canada, the United States, and Scotland, revealing that approximately 1 in 400 people (0.246%) has a CAG repeat of 36 or greater. This frequency of the HD mutation in the general population is higher than expected from clinical prevalence estimates. The normal CAG repeat distribution was characterized in a range of ethnically distinct populations, allowing comparative estimates of the HD new mutation rate. Estimated as a function of intermediate CAG repeat frequencies below the pathogenic range (27-35 CAG), 1 in 5372 births is a new mutation for HD in European ancestry populations, representing 7.1% of HD mutations (≥36 CAG) in the general population.

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Impact of Caspase-6 Modulation on Huntington Disease Phenotypes in the YAC128 Mouse Model (2016)

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. HD is caused by a CAG repeat expansion in the huntingtin (HTT) gene leading to the production of the mutant huntingtin protein (mHTT). Caspase-6 (C6) is a cysteine aspartyl protease that plays a central role in apoptosis and has been postulated to play a role in inflammation. Increased C6 activation is observed in human HD brains and mouse models and the inhibition of C6-mediated cleavage of mHTT protects against neuropathology and behavioural deficits in the YAC128 mouse model of HD. Additionally, alterations in inflammation are a feature of many neurodegenerative diseases, including HD. Hyperactive inflammatory responses are observed in both HD patients and mouse models and C6 has been postulated to play a role in mediating inflammation. Constitutive deletion of the Casp6 gene (denoted as C6) in YAC128 mice results in a partial rescue of some features of HD; however, the continued presence of the 586 cleavage fragment in the absence of C6 suggests possible compensation by other proteases. The goal of this thesis was to investigate the impact of modulating C6 in the adult YAC128 mouse and to further characterize the role of C6 in inflammation. To that end, the C6 gene was partially deleted in the adult YAC128 mouse and characterization of these mice reveals no amelioration in motor or cognitive phenotypes but a modest improvement in certain psychiatric behaviours. Neuropathological assessment shows no attenuation in canonical brain pathology but peripherally, the loss of C6 attenuates the overactive inflammatory response observed in YAC128 mice. These data suggest that partial loss of C6 in the brain is not sufficient to improve most behavioural and neuropathological phenotypes but implicate C6 in the regulation of inflammation. Furthermore, loss of C6 results in a blunted inflammatory response characterized by reduced cytokine release. As the presence of elevated cytokine levels have been suspected to cause psychiatric behaviours such as depression, this finding provides a possible mechanistic link between C6 activity and the onset of affective behaviours.

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The role of palmitoylation in the pathogenesis of Huntington disease (2015)

Huntington disease (HD) is caused by a CAG expansion in HTT characterized by motor, cognitive, and psychiatric disturbances. Huntingtin Interacting Protein 14 (HIP14) and HIP14-like (HIP14L) are palmitoyl acyltransferases (PATs) that mediate the post-translational addition of fatty acids to proteins (palmitoylation). They palmitoylate HTT and have reduced interaction with and palmitoylation of mutant HTT (mHTT), leading to increased mHTT inclusion formation and toxicity. HTT is essential for full enzymatic activity of HIP14 and loss of either of these genes leads to HD-like phenotypes. The goal was to determine the role of palmitoylation in the pathogenesis of HD. The overall hypothesis is that disturbed HIP14- and HIP14L-HTT interaction in HD reduces PAT function leading to the under-palmitoylation and mislocalization of HTT and key HIP14 and HIP14L substrates. Multiple putative PAT binding sites in HTT were identified, one around aa224 and one around aa427, that are required for full interaction but aa1-548 are required for the structural integrity of the binding sites. Loss of both Hip14 and Hip14l leads to embryonic lethality between day 10 and 11 in utero, due to failed placenta formation. Intriguingly, the extraembryonic tissue of Hip14-/-;Hip14l-/- embryos share many features with that of Htt-/- embryos and palmitoylation of HTT was decreased by 25% in Hip14-/-;Hip14l-/- mouse embryonic fibroblasts. Palmitoylation of mHTT, SNAP25, and PSD-95 was decreased in the YAC128, BACHD, and Hu97/18 mouse models of HD. The HD-like phenotype of the Hip14-/- mice is developmental and non-progressive, unlike the adult-onset, progressive phenotype of the YAC128 mice. Mice in which Hip14 deficiency is induced in adulthood show reduced survival, motor deficits, anhedonia, increased escape response, increased forebrain weight and cortical volume, and decreased corpus callosum volume. This indicates that loss of Hip14 from conception allows for developmental compensation that cannot occur if Hip14 deficiency occurs in the adult.

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Genetic counselling implications for intermediate allele predictive test results for Huntington Disease (2013)

Intermediate alleles (IAs) for Huntington disease (HD) have between 27–35 CAGrepeats. While they usually do not confer the HD phenotype, they are prone togermline CAG repeat instability. Consequently, offspring are at-risk of inheriting anexpanded allele in the HD range (≥36 CAG). Currently there are numerous gaps inour molecular and clinical knowledge on IAs despite their characterization almost 20years ago. This thesis utilized a unique mixed-method design of molecular andqualitative techniques in order to generate new knowledge on the frequency,haplotype, and CAG repeat instability of IAs and explored current geneticcounselling practices and patient understanding and interpretation of an IA predictivetest results (PTR).In the Huntington Disease Biobank at the University of British Columbia, 30%(n=54/181) of IA familial transmissions demonstrated intergenerational CAG repeatinstability. Of these unstable transmissions, 14% were repeat expansions into thedisease-associated range. In a sample of British Columbia’s general population, withno known association to HD, 5.8% (n=92/1594) of individuals were found to have anIA. Of the IAs ascertained in this general population sample, 60% were onhaplotypes associated with a high-risk of CAG repeat instability. Paternal CAG-sizespecific risk estimates for repeat instability, including repeat expansion into the HDrange, were established using sperm (n=18763) from 31 males with an IA. Alleles atthe upper limits of the intermediate CAG size range (34-35 CAG) had the mostsignificant risk (i.e. 2.5-21.0%) of expanding into the disease range. Interviews withmedical genetics service providers and individuals who received an IA-PTR revealedpre-test genetic counselling practices vary based on the individuals’ family historyand that clients struggled to understand the clinical implications and significance oftheir IA-PTR.This thesis substantially contributes to our knowledge of IAs for HD. Collectively thecomprehensive findings have important implications for genetic counselling and willhelp ensure individuals undergoing predictive testing receive appropriate support,education, and counselling on IAs.

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The biology and expression of huntingtin interacting protein 14 (2013)

Huntingtin Interacting Protein 14 (HIP14) is a palmitoyl acyl transferase (PAT)that was first identified due to altered interaction with mutant huntingtin, theprotein responsible for Huntington Disease. HIP14 palmitoylates a specific set ofneuronal substrates critical at the synapse, and downregulation of HIP14 bysiRNA in vitro results in increased cell death in neurons. Recent findings haverevealed that mice lacking murine Hip14 (Hip14-/-) demonstrate a Huntington-Disease-like phenotype. In the current study, we have generated andcharacterized human HIP14 BAC transgenic mice. We generated humanizedHIP14 transgenic mice by crossing the HIP14 BAC mouse to the Hip14-/- model.Rescue of the Hip14-/- phenotype indicates that the defects seen in Hip14-/- miceare in fact due to loss of HIP14. In addition, our findings indicate human HIP14can compensate for the loss of the murine ortholog, and that very low levels ofHIP14 are sufficient to rescue the Hip14-/- phenotype. Finally, we assesspatterns of HIP14 expression in early development. Our findings further ourunderstanding of HIP14 in vivo, and point to several potential avenues for futurestudies.

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The post-transcriptonal regulation of ABCA1 (2013)

Epidemiological studies consistently demonstrate an inverse relationship between HDL levels and cardiovascular disease (CVD), independent of LDL and triglyceride levels. Due to the crucial role ABCA1 plays in HDL biogenesis, increasing ABCA1 expression is considered an attractive strategy to increase plasma HDL levels. In this thesis we attempt to identify novel post-transcriptional and post-translational mechanisms that regulate ABCA1 expression and/or function. Prior to translation, ABCA1 protein expression is regulated by non-coding RNA molecules known as microRNAs which bind and inhibit translation of mature mRNA transcripts in the cytoplasm. In this study we used bioinformatic prediction programs to identify potential microRNA regulators of ABCA1. Using reporter constructs, protein expression analysis by immunoblotting, and cholesterol efflux assays, we validated microRNA-145 as a novel repressor of ABCA1 translation. The inhibition of endogenous microRNA-145 in HepG2 cells increases both ABCA1 protein levels and cholesterol efflux activity. The inhibition of this microRNA in the liver is a potential strategy to increase HDL levels. Following translation, numerous post-translational modifications and protein-protein interactions are required for the ABCA1 protein to function properly. In this study we identified palmitoylation as a novel post-translational modifier of ABCA1. The majority of ABCA1-mediated cholesterol efflux and HDL biogenesis occurs at the cell surface. We show that palmitoylation is a crucial lipid addition for proper ABCA1 plasma membrane localization. We also identify a number of enzymes that mediate the incorporation of radio-labeled palmitate onto ABCA1, and demonstrate that the overexpression of the palmitoyl transferase enzyme DHHC8 increases ABCA1 palmitoylation and cholesterol efflux activity. The increase of ABCA1 palmitoylation in the liver is a novel strategy to increase HDL levels. In this thesis, we have contributed to the understanding of ABCA1 biology by the identification of two novel regulators of ABCA1 expression and/or function.

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Addressing Access to Huntington Disease Predictive Testing (2012)

Genetic knowledge holds great promise in terms of health benefits, yet also raises challenges regarding the delivery of beneficial testing and services. Addressing this challenge is especially important in rural areas where lack of access to clinical genetics is pervasive, resulting in considerable inequities in service availability. The purpose of this research study is to explore the hypothesis that a novel telehealth strategy for delivering predictive testing (PT) for Huntington disease (HD) can address the potential inequity that exists in access to PT in rural communities in British Columbia. To address the hypothesis, the project employed a three part, highly structured, mixed method sequential exploratory approach. The first part of the research involved: a) a mapping study; b) a qualitative interview study of 33 at-risk individuals; c) a survey of 102 individuals at-risk for HD; and d) an 11-person expert workshop. The second part of the research built on results from the prior work and was to develop a telehealth PT protocol and a HD PT dedicated website for individuals considering testing. The final component of the research involved a pilot project that compared the novel telehealth protocol with the standard, Vancouver-based PT protocol. Evaluation of the pilot project was conducted by quantitative survey with 28 participants and was subject to statistical analysis. Results revealed that PT rates are lower in rural areas and that access is a significant issue due to distance related factors and the inflexible nature of the PT process. The pilot project demonstrated that providing PT via telehealth is not only possible, but is also warranted. There were no significant differences in terms of quality of care, information, counseling and support during the PT process between the Vancouver-tested and telehealth-tested groups. Overall, the pilot study reveals that providing PT via telehealth can improve access to PT while maintaining high quality of care and support. The work adds to a growing body of literature on the utility of telehealth services in genomic medicine in an age of increased technological innovation and comfort with such communication mechanisms.

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Assessment of novel therapeutic approaches in the YAC128 mouse model of Huntington disease (2010)

Huntington disease (HD) is a progressive disorder characterized by involuntary movements, emotional disturbances, and memory loss. There is currently no cure for HD. Accumulating evidence has implicated excitotoxicity, a process in which excessive signaling via the glutamate receptors results in neurotoxicity, in HD. The main aim of the studies presented was to evaluate the potential of small molecules known to target excitotoxicity-related pathways in the YAC128 mouse model of HD. We examined whether treatment with memantine, a clinically well-tolerated NMDA receptor antagonist, can improve the phenotype of YAC128 mice. We demonstrated that treatment with memantine results in improvements in motor function and rescues the striatal deficits in a dose-specific manner. Rasagiline is a selective inhibitor of monoamine oxidase type B (MAO-B) clinically approved for the treatment of Parkinson’s disease that has been shown to protect against a number of neurotoxic stimuli. We demonstrate that rasagiline protects against striatal lesioning in acute models of excitotoxicity and improves the motor function of the YAC128 mice. We next examined the effect of treatment with a combination of memantine and rasagiline on the phenotype of the YAC128 mice. We demonstrate that treatment with a combination of memantine and rasagiline provides early and sustained improvements in motor function and rescues striatal deficits in the YAC128 mice. Induction of a heat shock protein (HSP) response has been shown to be neuroprotective in models of excitotoxicity and polyglutamine-induced neurodegenerative disease. We examined whether treatment with arimoclomol, a compound shown to enhance the HSP response, can improve the phenotype of the YAC128 mice. Our findings demonstrate that treatment with arimoclomol does not lead to up-regulation of an HSP response or rescue of the behavioural and striatal deficits in the YAC128 mice. Finally, we characterize psychiatric disturbances in YAC128 mice, demonstrating that YAC128 mice exhibit depressive-like symptoms as assessed by the Porsolt forced swim test and the sucrose consumption test of anhedonia. These measures may be employed in assessing any anti-depressive effects of candidate treatments in preclinical therapeutic trials. Our findings suggest that targeting excitotoxicity may be a viable therapeutic approach in HD.

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The role of caspase-2 in the progression of Huntington disease in the YAC128 mouse (2010)

No abstract available.

Identification of novel palmitoyl acyl transferases and characterization of the role of Huntingtin palmitoylation in Huntington Disease (2008)

In neurons, modification by the lipid palmitate regulates trafficking and function of signaling molecules, neurotransmitter receptors and associated synaptic scaffolding proteins. HIP14 (huntingtin interacting protein 14) is the first identified and characterized mammalian palmitoyl transferase that regulates this process. I have shown that HIP14 has striking effects on modulating trafficking and function of many proteins important for synapse formation and plasticity such as PSD-95, a postsynaptic scaffolding molecule.The importance of the finding that HIP14 is a neuronal palmitoyl transferase is further emphasized by our recent discovery that huntingtin protein folding, trafficking and function are regulated by the enzyme HIP14. Expansion of the polyglutamine tract in huntingtin as seen in Huntington Disease (HD) results in reduced association with HIP14 and decreased palmitoylation of huntingtin, which contributes to the formation of inclusion bodies and enhanced neuronal toxicity. By manipulating HIP14 levels through expression or knockdown, we can manipulate the number of huntingtin inclusion bodies and neuronal cell viability. Overall, these discoveries offer novel mechanism for HD pathogenesis and provide new approaches to therapy for HD.The tight association of HIP14 with wild-type huntingtin, which differs from other known enzyme-substrate interactions, indicates that huntingtin serves other functions beyond being a substrate of HIP14. I have discovered that, in vitro, wild-type huntingtin may facilitate activity of HIP14 to palmitoylate other neuronal substrates such as SNAP25, PSD95 and GAD65. By contrast, mutant htt does not act this way, probably due to lack of interaction with HIP14. Furthermore, immunoprecipitated HIP14 from huntingtin+/- mice also exhibits less enzyme activity in palmitoylating GST-SNAP25 in vitro, suggesting that decreased huntingtin expression compromises HIP14 activity. In vivo, using Acyl Biotin Exchange assay, I have also found that palmitoylation of a number of presynaptic and postsynaptic proteins that are involved in neurotransmission are reduced in huntingtin+/- mice. This study not only ascribes an important biochemical function to wild-type huntingtin, but also suggests that defects in protein palmitoylation in general due to mutant huntingtin lack of ability to facilitate HIP14 activity may contribute to the pathogenesis of HD.

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The nature and extent of genetic discrimination among persons at risk for Huntington disease (2008)

Huntington disease (HD), the “Dancing Mania” of the Middle Ages, has always been aparticular target of social stigma and discrimination. With the discovery of a polymorphic DNAmarker linked to HD in 1983, individuals at-risk for HD were able to learn whether or not theyhad inherited the causative HD mutation and possibly escape its stigma and discrimination. Forthose who had inherited the HD mutation increased discrimination became a real possibility.Genetic discrimination (GD) refers to the differential treatment of asymptomaticindividuals or their family based on genetic differences. It has been over twenty years since theintroduction of predictive testing (PT) for HD, yet little is known about the nature and extent ofGD and whether PT actually results in increased levels of GD. The objective of this dissertationwas to use qualitative and quantitative methods to investigate the nature and extent of GDamong persons at-risk for HD.Qualitative findings provide insight into how individuals interpret, personalize andmanage GD. Results from the national survey indicate that 40% of respondents reported atleast one experience of GD. Reported experiences occurred most often in reference to life anddisability insurance, and among family and friends. Surprisingly, there were few reports of GD inemployment, health care and government settings. Experiences were not significantlyassociated with PT. However, the proportion of respondents who reported GD was 16% higheramong persons who have the HD mutation than among those that do not and untestedrespondents. Interestingly, respondents’ family history (FH), rather than their PT result, was themajor reason given for their experiences as well as an important predictor of GD. Psychologicaldistress was a health outcome of GD.This is the first study to investigate the nature and extent of GD among an asymptomatictested and untested population. This dissertation provides evidence that GD is a frequentlyreported experience and a source of distress for persons at-risk for HD. These findings provideinsight for policy, identify areas where more education and support is needed, and providedirection to genetic professionals supporting their clients as they confront issues of GD.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Genome-Wide Association Study of Cisplatin-Induced Hearing Loss in Children (2014)

Cisplatin is an effective chemotherapeutic agent used for a variety of solid organ malignancies in children and adults. However, its clinical use is limited by the high incidence of cisplatin-induced ototoxicity (CIO), which can affect up to 40-60% of children treated. To date, the genetic basis for CIO has been studied with only focused candidate-gene approaches. Here we report the findings of the first genome-wide association study (GWAS) of cisplatin-induced ototoxicity in children. We examined 738,432 genetics markers in a discovery cohort of 282 Canadian paediatric patients treated with cisplatin, followed by a replication study in an independent Canadian cohort of 82 children. In addition, clinical, therapeutic, and demographic characteristics of cases and controls were analysed to identify clinical factors that may also contribute to the susceptibility to CIO. The genome-wide analyses identified a significant association within the toll-like receptor 4 (TLR4) gene on chromosome 9. The most highly associated single nucleotide polymorphism (SNP) rs960312 conferred a highly protective effect against cisplatin-induced hearing loss (P = 1.19x10-⁸ , odds ratio = 0.22). This variant was subsequently replicated in an independent paediatric cohort (P = 0.018, odds ratio = 0.25). This variant is a tag SNP for a TLR4 promoter haplotype reported to have significantly altered transcriptional efficiency of TLR4. In both cohorts, CIO is significantly associated with younger age (P = 3.41x10-⁶), concomitant vincristine use (P = 2.03x10-¹²), and germ-cell tumour type (P = 4.50x10-⁶). After correcting for these clinical factors, TLR4 rs960312 remains highly associated (Uncorrected P = 1.16x10-⁹ ; Corrected P = 1.01x10-⁹). Several lines of evidence from in vitro and in vivo studies have implicated TLR4 in cisplatin-induced cochlear toxicity and hearing loss. Here we provide the first evidence linking TLR4 and CIO in human patients treated for cancer, leading to new insights into the mechanism underlying this pervasive and clinically limiting adverse drug reaction. The identification of additional markers that contribute to the susceptibility of CIO can be used to develop individualized patient treatments, which can potentially improve safety and treatment outcome of cisplatin.

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The Role of Sterol 12a-hydroxylase (Cyp8b1) in Glucose Homeostasis (2014)

Besides their role in facilitating lipid absorption, bile acids are increasingly being recognized as signaling molecules that activate cell-signaling receptors. Targeted disruption of cytochrome P450 sterol 12α- hydroxylase (Cyp8b1) results in complete absence of cholic acid and its derivatives. The impact of Cyp8b1 deletion has predominantly been studied with respect to development of atherosclerosis and lipid and bile acid metabolism. Here, for the first time, we investigate the impact of Cyp8b1 deletion on glucose homeostasis. Absence of Cyp8b1 results in improved glucose tolerance, enhanced insulin sensitivity and improved β-cell function in Cyp8b1-/- mice. In addition, our results show that reduced intestinal fat absorption in the absence of biliary cholic acid in Cyp8b1-/- mice leads to increase in free fatty acids reaching the ileal L-cells. This increase in the luminal free fatty acids correlated with significantly increased secretion of the incretin hormone, glucagon like peptide-1 (GLP-1). GLP-1 in turn increases the biosynthesis and secretion of insulin from β-cells, leading to the improved glucose tolerance observed in the Cyp8b1-/- mice. Treatment of Cyp8b1-/- mice with Exendin (9-39) amide, a potent and selective GLP-1 receptor antagonist, restored their glucose tolerance to control levels. Furthermore, cholic acid feeding in Cyp8b1-/- mice resulted in complete normalization of not only fat and glucose tolerance, but also GLP-1 secretion. These data suggest that the absence of cholic acid leads to the improvement in the glycemic control of Cyp8b1-/- mice. Thus, our data demonstrates the importance of Cyp8b1 inhibition in the regulation of glucose metabolism.

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The Epidemiology of Huntington Disease in British Columbia (2012)

Introduction: Global prevalence estimates for Huntington Disease (HD) vary widely, and those cited for Canada are outdated and not specific to British Columbia (BC). The most recent incidence calculation was performed in BC and includes diagnoses only up to the year 1999. Reports on the population at risk in Canada are based on theories and estimates that do not pertain to any particular population. Despite the presence of an extensive laboratory and clinical research hub in this province, a comprehensive epidemiological study of the prevalence, incidence and population at risk for HD has never been assessed. As such, the specific objectives of this study were to: 1) Calculate the minimum prevalence of HD in BC on April 1, 2012; 2) Calculate the incidence of HD in BC from January 1, 2001- December 31, 2011; and 3) Calculate the minimum population at risk for HD in BC on April 1, 2012. Methods: A comprehensive province-wide assessment of the HD patient population and the population at risk was conducted using multiple sources of ascertainment including: UBC HD clinic records, hospital and physician records, DNA diagnostic lab reports, the HD research lab at the Centre for Molecular Medicine and Therapeutics (CMMT), nursing homes, The Huntington Society of Canada and HD community members. Results: The minimum prevalence of HD in BC was estimated at 12.5 - 14.9/100,000 (95% CI: 11.5-16.0) (1/8,697 – 1/6,250), the incidence, 7.2 per million/year (95% CI: 6.5-7.9), and the minimum population at risk: 1/1,064 (95% CI: 1/1,941 - 1/2,107).Conclusions: The prevalence of HD is nearly twice as high as suggested by a previous Canadian report. This study comprised the most thorough HD patient ascertainment study since the advent of direct mutation testing and may set a precedent for future prevalence studies. Incidence has remained the same since 1999 and BC is only the fourth region in the world to provide a direct estimate of the population at risk for HD.

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The Pharmacogenomics of Cisplatin-induced Hearing Loss (2012)

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumours. A serious complication of cisplatin treatment is permanent hearing loss. The study hypothesis is that genetic variants in genes involved in drug metabolism and transport can contribute to increased susceptibility to hearing loss in pediatric oncology patients treated with cisplatin. Patients were recruited from across Canada through the Canadian Pharmacogenomics Network for Drug Safety (CPNDS). Recently, our group identified several predictive genetic variants that were highly associated with cisplatin-induced hearing loss in children. We evaluated whether we could replicate these findings in a new independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P=0.0013, Odds Ratio, OR 6.1) and ABCC3 (rs1051640, P=0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3 and COMT with clinical variables significantly improved the prediction of risk of developing hearing loss compared to clinical risk factors alone (P=0.00048). We next evaluated whether we could identify additional genetic variants that confer susceptibility to cisplatin-induced hearing loss. We identified novel variants in ABCB5 (rs10950831, P=1.06×10⁻⁶, OR 2.0) and DPYD (rs6667550, P=0.0047, OR 1.9) that were significantly associated with cisplatin-induced hearing loss. We included these variants into the initial genetic model that consists of variants in TPMT, ABCC3 and COMT to evaluate whether we could improve the prediction of risk. We demonstrate that the risk of prediction of hearing loss significantly improves by including genetic variants in ABCB5 and DPYD (P=0.0023). We also demonstrate that by combining the clinical and genetic factors we can significantly improve the prediction of risk of hearing loss compared to clinical factors alone (P=2.63x10⁻⁷). We were able to replicate previously described findings and also provide evidence for novel genetic variants in the prediction of cisplatin-induced hearing loss in children. Furthermore, this study demonstrates that predictive models can classify patients based on predicted risk of cisplatin-induced hearing loss. These findings have the potential to influence treatment modifications for cisplatin therapy and may improve safety in children.

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Characterization of constitutive caspase-6 deficient mice: Insights into axonal degeneration, excitotoxicity and age dependent behavioral and neuroanatomical changes (2011)

Apoptosis or programmed cell death is a cellular pathway involved innormal cell turnover, developmental tissue remodeling, embryonic development,cellular homeostasis maintenance and chemical-induced cell death. Caspases are a family of intracellular cysteine-aspartic proteases that play a key role inprogrammed cell death. Aside from their roles during development, aberrant activation of caspases has been implicated in several human diseases. In particular, numerous findings implicate Caspase-6 (Casp6) in neurodegenerative diseases highlighting the need for a deeper understanding of Casp6 biology andits role in brain development.The use of targeted caspase deficient mice has been instrumental for studying the involvement of caspases in apoptosis. The goal of this study was to perform an in depth neuropathological and behavioral characterization ofconstitutive Casp6-deficient (Casp6 -/-) mice in order to understand the physiological function of Casp6 in brain development, structure and function and to establish if any biological effects are caused by ablation of Casp6. We demonstrate that Casp6 -/- neurons are protected against NMDAmediatedexcitotoxicity and NGF-deprivation induced axonal degeneration.Furthermore, Casp6 deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype anddisplay learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the Casp6 -/- mice suggest that Casp6deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in Huntington disease and thecortex in Alzheimer Disease. These results provide further insights into the role of Casp6 in neurodegenerative diseases.

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