A5023440671- Alzheimer's disease research and treatments
- Parkinson's Disease Mechanisms and Treatments
- Nuclear Receptors and Signaling
- Pluripotent Stem Cells Research
- 3D Printing in Biomedical Research
- Cellular transport and secretion
- Lysosomal Storage Disorders Research
- Tissue Engineering and Regenerative Medicine
- Barrier Structure and Function Studies
- Single-cell and spatial transcriptomics
- Nerve injury and regeneration
- Neuroscience and Neural Engineering
- Neurological diseases and metabolism
- Medicinal Plants and Neuroprotection
- RNA regulation and disease
- Neuroinflammation and Neurodegeneration Mechanisms
- Prion Diseases and Protein Misfolding
- Neurological Disorders and Treatments
- Endoplasmic Reticulum Stress and Disease
- Diabetes, Cardiovascular Risks, and Lipoproteins
- CRISPR and Genetic Engineering
- Advanced Glycation End Products research
- Hemispheric Asymmetry in Neuroscience
- Gene expression and cancer classification
- Cerebrovascular and genetic disorders
University of Oxford
2009-2024
University of British Columbia
2019-2022
Vancouver Coastal Health
2020
Centre for Human Genetics
2006-2007
Abstract We describe a human single-nuclei transcriptomic atlas for the substantia nigra (SN), generated by sequencing approximately 17,000 nuclei from matched cortical and SN samples. show that common genetic risk Parkinson’s disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression, including mitochondrial functioning, protein folding ubiquitination pathways. identify distinct cell type association between PD oligodendrocyte-specific expression. Unlike Alzheimer’s...
Neurofibrillary tangles composed of exon 10+ microtubule associated protein tau (MAPT) deposits are the characteristic feature neurodegenerative diseases progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). PSP, CBD more recently Alzheimer's disease Parkinson's disease, with MAPT H1 haplotype, but relationship between genotype remains unclear. Here, we investigate hypothesis that expresses mRNA compared to other H2, leading a greater susceptibility neurodegeneration in...
Variants at the GBA locus, encoding glucocerebrosidase, are strongest common genetic risk factor for Parkinson's disease (PD). To understand GBA-related mechanisms, we use a multi-part-enrichment proteomics and post-translational modification (PTM) workflow, identifying large numbers of dysregulated proteins PTMs in heterozygous GBA-N370S PD patient induced pluripotent stem cell (iPSC) dopamine neurons. Alterations glycosylation status show disturbances autophagy-lysosomal pathway, which...
Alzheimer's disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation extracellular plaques intracellular neurofibrillary tangles that mainly consist amyloid-β (Aβ) hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out microtubule-associated protein (Mapt) gene demonstrated Aβ-driven toxicity tau-dependent. However, human cellular chronic lowering remain...
The H1 haplotype of the microtubule-associated protein tau (MAPT) locus is genetically associated with neurodegenerative diseases, including Parkinson's disease (PD), and affects gene expression splicing. However, functional impact on neurons such differences has yet to be fully elucidated. Here, we employ extended maturation phases during differentiation induced pluripotent stem cells (iPSCs) into mature dopaminergic neuronal cultures obtain expressing all six adult isoforms. After 6 months...
The PDMS-based microfluidic organ-on-chip platform represents an exciting paradigm that has enjoyed a rapid rise in popularity and adoption. A particularly promising element of this is its amenability to manufacturing strategies, which can enable quick adaptations through iterative prototyping. These however, come with challenges; fluid flow, for example, core principle organs-on-chip the physiology they aim model, necessitates robust, leak-free channels potentially long (multi-week) culture...
Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer's disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms which HDL improve cerebrovascular functions relevant to AD remain poorly understood.Here we use a human bioengineered model cerebral amyloid angiopathy (CAA) define several Aβ within vasculature attenuates endothelial inflammation as measured monocyte binding.We demonstrate accumulation...
The neurovascular unit (NVU) - the interaction between neurons and cerebrovasculature is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in last decade, there currently no vitro 3-dimensional (3D) perfusible model human cortical arterial NVU.We used a tissue-engineering technique develop scaffold-directed, perfusible, 3D NVU that cultured native-like flow conditions mimics anatomy physiology...
The microtubule-associated protein tau (MAPT or tau) is of great interest in the field neurodegeneration as there a well-established genetic link between MAPT gene locus and tauopathies, diverse group neurodegenerative dementias movement disorders. genomic architecture region spanning contains ~1.8 Mb block linkage disequilibrium characterized by two major haplotypes: H1 H2. Recent studies have established strong association disease uncovered haplotype-specific differences expression...
Genome wide association studies have identified microtubule associated protein tau (MAPT) H1 haplotype single nucleotide polymorphisms (SNPs) as leading common risk variants for Parkinson's disease, progressive supranuclear palsy and corticobasal degeneration. The MAPT fall within a large 1.8 Mb region of high linkage disequilibrium, making it difficult to discern the functionally important variants. Here, we leverage strong haplotype-specific expression exon 3 investigate functionality SNPs...
Abstract We describe a human single-nuclei transcriptomic atlas for the Substantia nigra ( SN) , generated by sequencing ~ 17,000 nuclei from matched cortical and SN samples. show that common genetic risk Parkinson’s disease PD ) is associated with dopaminergic neuron DaN )-specific gene expression, including mitochondrial functioning, protein folding ubiquitination pathways. identify distinct cell type association between oligodendrocyte-specific expression. Unlike Alzheimer’s AD ), we find...
The H1 Haplotype of the microtubule associated protein tau (MAPT) locus is genetically with neurodegenerative diseases, including Parkinson's disease, progressive supranuclear palsy and corticobasal degeneration (CBD), affects gene expression splicing. However functional impact haplotype-specific sequence in neurons has yet to be fully elucidated. Here, we differentiated dopaminergic neuronal cultures from induced pluripotent stem cells (iPSCs) heterozygous for MAPT H1/H2 haplotypes three...
Abstract The causes of Parkinson’s disease (PD) likely involve complex interactions between environmental factors and susceptibility genes with variants at the GBA locus encoding glucocerebrosidase (GCase) enzyme being strongest common genetic risk factor for PD. To understand -related mechanisms, we used a novel multipart-enrichment proteomics post-translational modification workflow to simultaneously identify peptides phosphorylation, reversible cysteine-modifications or sialylated...
Abstract Background Several lines of evidence suggest that high‐density lipoprotein (HDL) reduces Alzheimer’s disease (AD) risk by decreasing vascular beta‐amyloid (Aβ) deposition and inflammation, however, the mechanisms which HDL improve cerebrovascular functions relevant to AD remain poorly understood. Methods Here we use a human bioengineered model cerebral amyloid angiopathy (CAA) define several Aβ within vasculature attenuates endothelial inflammation as measured monocyte binding....
Abstract Background Alzheimer’s disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation extracellular plaques intracellular neurofibrillary tangles that mainly consist amyloid-β (Aβ) hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out microtubule-associated protein (Mapt) gene demonstrated Aβ-driven toxicity tau-dependent. However, human cellular...
Two major haplotypes have been defined spanning the microtubule associated protein tau (MAPT) genomic locus, H1 and H2, of which is with Parkinson's disease progressive supranuclear palsy. Despite consistent strong association haplotype tauopathies, mechanisms by polymorphisms confer susceptibility to neurodegeneration not defined. One theory explain neurodegenerative MAPT proposes that there are overall expression differences between two influenced variants within promoter region. The aim...
Two major haplotypes have been defined spanning the MAPT genomic locus, H1 and H2, of which haplotype is associated with progressive supranuclear palsy, corticobasal Alzheimer's disease. Despite consistent strong association tauopathies, polymorphisms confer susceptibility to neurodegenerative disease not defined. Recently, studies looked at functional effects haplotype, focusing particularly on overall tau expression splicing neuropathologically relevant exon 10. We shown that significantly...