Blair Leavitt


Research Interests

Alzheimer's disease
Amyotrophic Lateral Sclerosis
Experimental Therapeutics
Frontotemporal Dementia
Gene regulation
Gene Silencing and Gene Editing
Gene Therapy
Huntington disease
Induced Pluripotent Stem Cells
Medical Genetics
Mouse models of disease
Neurodegenerative diseases

Relevant Degree Programs



Master's students
Doctoral students
Postdoctoral Fellows

Mouse models of neurodegenerative diseases
Clinical biomarkers of neurodegenerative diseases (Imaging, CSF, Blood)
Gene silencing, gene editing and gene therapy for brain diseases
Transcriptional regulation of disease genes
Experimental therapeutics for neurodegenerative diseases
Induced pluripotent stem cells models of human brain diseases

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Postdoctoral Fellows

Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Nov 2020)
Investigating vitamin B6-dependent epileptic encephalopathies in human patients and a mouse model (2020)

PLPHP deficiency is a recently discovered form of vitamin B6-dependent epilepsies (B6Es) that is caused by recessive mutations in PLPBP. PLPHP is involved in pyridoxal 5’-phosphate (PLP) homeostatic regulation. However, the mechanism by which PLPHP dysfunction disrupts PLP homeostasis and leads to the observed encephalopathy in patients was still elusive. We characterized the clinical, genomic and biochemical abnormalities in a new series of 12 PLPHP deficiency patients. Our results identified previously undescribed clinical features of PLPHP deficiency, including non-epileptic movement disorder, fatal mitochondrial encephalopathy and folinic acid-responsive seizures. We characterized the pathogenicity of patients’ PLPBP variants using in silico tools and 3D modelling of PLPHP and developed a system of clinical severity score. We generated and characterized PLPBP knockout models in HEK293 cells, yeast and zebrafish. Our plpbp-KO zebrafish model replicated the clinical phenotype of PLPHP-deficient patients by showing vitamin B6-dependent seizures and death in untreated KO larvae. Consistent with the biochemical picture in patients, Plphp-deficient fish displayed decreased systemic levels of PLP. In the future this model can be utilized as a tool for investigating the disease pathophysiology, drug screening and identifying diagnostic biomarkers. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is another form of B6Es that is caused by mutations in ALDH7A1, a gene which encodes an enzyme within the lysine catabolism pathway. We have successfully generated and characterized transgenic mouse strain with constitutive genetic ablation of Aldh7a1. Results showed that KO mice accumulated high concentrations of upstream lysine metabolites including ∆¹-piperideine-6-carboxylic acid (P6C), α-aminoadipic semialdehyde (α-AASA) and pipecolic acid (PIP), similar to the biochemical picture in ALDH7A1-defiecint patients. KO mice fed the regular diet (0.9% lysine) did not exhibit seizures based on EEG analysis. When KO mice are switched to a diet containing higher amount of lysine (4.7%), they developed severe recurrent seizures which led to their quick death. In analogy to the patients’ picture also, treating KO mice under high lysine diet with pyridoxine injections prevented seizures and prolonged their survival. This study provides a proof-of-concept for the utility of the model to study PDE-ALDH7A1 biochemistry and to test new therapeutics.

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Microglial Dysfunction Induced by Mutant Huntingtin (2016)

Huntington’s disease (HD) is a devastating, late-onset neurodegenerative disorder that causes profound behavioral abnormalities, language impairment, and alterations in personality in affected patients. HD is an autosomal dominantly inherited disease, caused by a CAG trinucleotide repeat expansion in the huntingtin gene. HD effects up to 1 in 10,000 in populations of European ancestry, but with at least a 10 fold reduced prevalence rate in individuals in Asian or African descent. The critical mechanisms by which the expansion in the huntingtin gene leads to selective neurodegeneration in HD are poorly understood. The purpose of this thesis was to better understand the microglial dysfunction caused by mutant huntingtin and the potential role this microglial dysfunction may play in the pathogenesis of HD. Huntingtin, the protein (HTT) expressed from the huntingtin gene, is ubiquitously expressed in many tissues, with the highest expression levels in brain and testis. Over the last 20 years there have been multiple scientific breakthroughs allowing the development of an array of model systems to investigate HD pathogenesis. Immune dysfunction has recently been implicated in a number of neurodegenerative diseases, including HD. In conclusion, the mechanism of neurodegeneration is not well understood in HD, inflammation could play a pivotal role in the progression of the disease. Inflammation is altered in immune cells containing mutant HTT (mHTT), and although I was unable to provide conclusive evidence that mHTT-induced microglial dysfunction and related neuroinflammation are required for neurodegeneration in an HD mouse model, my work highlights the importance of critically evaluating proposed new disease mechanisms as many will not be directly involved in HD neurodegeneration. My research provides concrete evidence that immune dysfunction occurs in monocyte cells expressing mHTT, however, this cell intrinsic dysfunction does not play a major role in the HD phenotype of the BACHD mouse model.

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Characterization of the Huntingtin Gene Promoter and Huntingtin Transcriptional Regulation (2015)

Huntington’s disease (HD) is a late onset, neurological, autosomal dominant genetic disorder. Despite being associated to a defined genetic mutation within the huntingtin gene (HTT), little is known about its transcriptional regulation. HTT is expressed, at varying levels, throughout the body. At the current time, the transcriptional regulation mechanisms controlling this differential expression pattern are unknown. Previous studies have focused on the genomic region directly preceding HTT’s transcriptional start site. The purpose of this thesis was to utilize the current understanding of mammalian transcriptional regulation to further characterize the HTT promoter and to expand the search for transcriptional regulatory regions outside the promoter. To direct this search a bioinfomatic screen was conducted, which identified 11 putative regions. Potential transcription factor binding sites (TFBSs) within these regions were identified through the use of available chIP-seq datasets. Curation of the TFBSs within the putative regions lead to selection of the 9th region, in addition to the promoter, for further study. To test the functionality of region 9 and identified candidate transcription factors (TFs), a panel of human kidney and rat neuronal cell lines were established. These cell lines stably expressed either the HTT promoter or region 9 luciferase constructs. Candidate TFs were tested using siRNA mediated knockdown. Knockdown of selected candidate TFs did not modulate HTT promoter function. The role of DNA methylation on transcriptional regulation of HTT was also explored using the Illumina 450K Methylation Array. Tissue specific DNA methylation of HTT using human cortex and liver tissues identified 33 differentially methylated sites. The role of the HD mutation on local and global DNA methylation was also investigated, finding no changes to local DNA and 15 differentially methylated regions globally. In conclusion, a data driven bioinfomatic search has expanded potential regulatory regions beyond that of the promoter of the HTT gene. A first attempt at identifying crucial TFs involved in HTT regulation was not successful, however additional candidates remain to be tested. A role for DNA methylation in tissue specific regulation of HTT has been identified, while the HD mutation itself does not appear to affect HTT DNA methylation.

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The role of progranulin in the brain (2014)

No abstract available.

Investigating the role of indoleamine 2,3 dioxygenase in Huntington disease (2013)

The striatum is predominantly affected in Huntington disease (HD). To address this selective degeneration, we previously studied the gene expression profile in mouse brain and compared the striatum to other brain regions to identify novel striatal-enriched genes. One identified gene was Indoleamine 2,3 dioxygenase (Ido1), the first and the rate-limiting enzyme of the kynurenine pathway (KP), which was differentially expressed in the striatum of YAC128 mouse model of HD. KP leads to the production of both neuroprotective and neurotoxic metabolites, the imbalance of which has been implicated in several neurodegenerative disorders. This PhD thesis initially focuses on the age-dependent changes of the KP in YAC128 mice with a main focus on Ido1 expression and activity. I was able to demonstrate a chronic induction of Ido1 expression and activity in the striatum of YAC128 mice, which correlated with different substrate or product levels during the course of the disease. Using a liquid chromatography mass spectrometry method, I was also able to identify changes in the downstream metabolites, which seemed to follow a biphasic pattern where neurotoxic metabolites were reduced in presymptomatic mice and increased in symptomatic mice. We propose that the striatal-specfic induction of Ido1 and downstream KP alterations suggest involvement in HD pathogenesis, and should be taken into account in future therapeutic developments for HD. To follow up, this thesis project also assesses the sensitivity of brain to NMDA-mediated excitotoxicity in the absence of Ido1 expression under in vivo and ex vivo settings. I was able to demonstrate decreased sensitivity to NMDA receptor-mediated neurotoxicity in the brain of Ido1 constitutive null mice compared to that of WT. These data suggest that lack of Ido1 expression in vivo provides protection against NMDA-receptor-mediated excitotoxic stress, a well-described mechanism in HD pathogenesis.

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Master's Student Supervision (2010 - 2018)
Quantifying iron levels in the YAC128 mouse model of Huntington's Disease (2014)

Huntington's Disease (HD) is one of many neurodegenerative diseases with reported alterations in brain iron homeostasis. Many neurodegenerative diseases exist which are characterized by brain iron accumulation. Whether elevated brain iron occurs in HD, and whether it plays a significant contributory role in pathogenesis or is a secondary effect is currently unclear. Iron accumulation in specific brain areas of neurodegeneration in HD has been proposed based on observations in post-mortem tissue and magnetic resonance imaging (MRI) studies. Altered MRI signal within specific brain regions undergoing neurodegeneration has been consistently reported and interpreted as altered levels of brain iron. Biochemical studies using various techniques to measure iron species in human samples, mouse tissue, or in vitro has generated equivocal data to support such an association. I have reviewed previous and current published literature reporting iron alterations and summarized the findings in this dissertation. Current consensus remains unclear if iron plays a contributing role, and further studies that modulate iron levels in HD models to assess the effects of iron are required.The experimental aim of this thesis was to measure iron-related changes in the YAC128 HD mouse model with the hypothesis that this mouse model will develop elevated striatal iron levels compared with wild-type littermates. Using analytical techniques to measure levels of elemental brain iron, no significant differences were observed in various brain regions of aged HD mice and in post-mortem HD samples.

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Generation and characterization of embryonic stem cell lines derived from the YAC128 mouse model of Huntington disease. (2010)

Huntington Disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the Huntingtin gene. Patients typically present in mid-life with progressive motor dysfunction, cognitive deficits, and neuropsychiatric abnormalities. Recently, researchers have provided evidence that HD is associated with significant pathology in peripheral tissues as well. At the current time no effective treatment has been proven to alter or cure progression of HD which leads to complete loss of independence and eventual death an average of 20 years after disease onset. The ability to model Huntington disease in animals has enabled studies which have provided new insights into the mechanisms of HD pathogenesis. However, the development of simple cell culture-based systems will be useful to accelerate our research efforts into the basic underlying pathogenic pathways of HD and will allow dissection of cellular interactions and the identification of novel targets for intervention that offer the greatest hope of a cure. The YAC mouse model of HD expresses full-length human Huntingtin with either 18 polyglutamines (YAC18) or 128 polyglutamines (YAC128), and develops age-dependent cognitive deficits, motor dysfunction, and selective striatal neurodegeneration similar to that seen in human HD patients. I have generated novel embryonic stem (ES) cell lines from wild-type, YAC18 and YAC128 mice on two genetic backgrounds. These cell lines have been cultured under defined conditions over long periods of time, and express characteristic markers of pluripotency, such as alkaline phosphatase, Oct-4 and Nanog. Neurons and macrophages derived from these novel cell lines using established in vitro protocols have been characterized via immunocytochemistry and challenged in functional assays.To confirm results attained from functional assays in our ES-derived macrophages, I examined primary macrophages and microglia cultures derived from the YAC mice and determined the functional response of these cells to endotoxin stimulation. Primary cell cultures isolated from YAC128 mice produced significantly more IL-6 than wild-type cultures. In comparison, with the same endotoxin stimulation, YAC18 primary macrophages and microglia responded with similar levels of IL-6 release as cultures of wild-type cells, suggesting that the over-activity in the YAC128 cytokine response is caused by the mutant Huntingtin transgene.

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