A5013832642- Prion Diseases and Protein Misfolding
- Trace Elements in Health
- Alzheimer's disease research and treatments
- Neurological diseases and metabolism
- RNA Research and Splicing
- RNA regulation and disease
- Advanced Proteomics Techniques and Applications
- Amino Acid Enzymes and Metabolism
- Amyloidosis: Diagnosis, Treatment, Outcomes
- CRISPR and Genetic Engineering
- Cellular transport and secretion
- RNA and protein synthesis mechanisms
- Computational Drug Discovery Methods
- Genetics and Neurodevelopmental Disorders
- Bioinformatics and Genomic Networks
- Animal Genetics and Reproduction
- Cholinesterase and Neurodegenerative Diseases
- Microtubule and mitosis dynamics
- S100 Proteins and Annexins
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA modifications and cancer
- Protein Structure and Dynamics
- Mitochondrial Function and Pathology
- Glycosylation and Glycoproteins Research
- Neurogenetic and Muscular Disorders Research
University of Toronto
2016-2025
Occupational Cancer Research Centre
2015-2025
Discovery Centre
2017-2023
Canada Research Chairs
2009-2023
German Center for Neurodegenerative Diseases
2012-2022
University Health Network
2009
Ontario Institute for Cancer Research
2007-2009
Princess Margaret Cancer Centre
2007
Cancer Institute (WIA)
2007
Toronto Western Hospital
2007
The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS FTD remain controversial. We propose a model low-complexity (LC) domains of drive its physiologically reversible assembly into membrane-free, liquid droplet hydrogel-like structures. ALS/FTD LC or non-LC induce further phase transition poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary sufficient for neurotoxicity C. elegans FUS-dependent neurodegeneration....
Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles is, part, driven by intrinsically disordered low-complexity (LC) domain FUS. Here, we report that cooperative cation-π interactions between tyrosines LC arginines structured C-terminal domains also contribute to separation. These are modulated post-translational arginine methylation, wherein hypomethylation strongly promotes gelation. Indeed, significant hypomethylation,...
In order to identify and compare the protein content of very low quantity samples high complexity, a protocol has been established that combines differential profiling strength new cleavable 13C isotope-coded affinity tag (cICAT) reagent with sequence coverage provided by multidimensional liquid chromatography two modes tandem mass spectrometry. Major objectives during optimization were minimize sample losses establish robust procedure employs volatile buffer systems are highly compatible...
Despite intense research efforts, the physiological function and molecular environment of amyloid precursor protein has remained enigmatic. Here we describe application time-controlled transcardiac perfusion cross-linking, a method for in vivo mapping interactions intact tissue, to study interactome (APP). To gain insights into specificity reported was extended mammalian precursor-like proteins (APLP1 APLP2). rule out sampling bias as an explanation differences individual datasets, small...
Epithelial ovarian cancer is the most lethal gynecological malignancy, and disease-specific biomarkers are urgently needed to improve diagnosis, prognosis, predict monitor treatment efficiency. We present an in-depth proteomic analysis of selected biochemical fractions human ascites, resulting in stringent confident identification over 2500 proteins. Rigorous filter schemes were applied objectively minimize number false-positive identifications, we only report proteins with substantial...
The tau protein is central to the etiology of several neurodegenerative diseases, including Alzheimer's disease, a subset frontotemporal dementias, progressive supranuclear palsy and dementia following traumatic brain injury, yet proteins it interacts with have not been studied using systematic discovery approach. Here we employed mild in vivo crosslinking, isobaric labeling, tandem mass spectrometry characterize molecular interactions human neuroblastoma cell model. study revealed robust...
Traditional drug development for Alzheimer's disease (AD) is costly, time consuming and burdened by a very low success rate. An alternative strategy repositioning, redirecting existing drugs another disease. The large amount of biological data accumulated to date warrants comprehensive investigation better understand AD pathogenesis facilitate the process anti-AD repositioning. Hence, we generated list protein targets analyzing most recent publically available 'omics' data, including...
There is growing evidence that zinc and its transporters are involved in cell migration during development cancer. In the present study, we show transporter ZIP10 (SLC39A10) stimulates motility proliferation, both mammalian cells zebrafish embryo. This associated with inactivation of GSK (glycogen synthase kinase)-3α -3β down-regulation E-cadherin (CDH1). Morpholino-mediated knockdown zip10 causes delayed epiboly deformities head, eye, heart tail. Furthermore, deficiency results...
Bank voles are susceptible to prion strains from many different species, yet the molecular mechanisms underlying ability of bank vole protein (BVPrP) function as a universal acceptor remain unclear. Potential differences in environments and interaction networks on cell surface brain cells may contribute BVPrP's unusual behavior. To test this hypothesis, we generated knock-in mice that express physiological levels BVPrP (M109 isoform) employed mass spectrometry compare interactomes mouse (Mo)...
In the more than twenty years since its discovery, both phylogenetic origin and cellular function of prion protein (PrP) have remained enigmatic. Insights into a possible PrP may be obtained through characterization molecular neighborhood in cells. Quantitative interactome data demonstrated spatial proximity two metal ion transporters ZIP family, ZIP6 ZIP10, to mammalian proteins vivo. A subsequent bioinformatic analysis revealed unexpected presence PrP-like amino acid sequence within...
The physiological environment which hosts the conformational conversion of cellular prion protein (PrP(C)) to disease-associated isoforms has remained enigmatic. A quantitative investigation PrP(C) interactome was conducted in a cell culture model permissive replication. To facilitate recognition relevant interactors, study extended Doppel (Prnd) and Shadoo (Sprn), two mammalian paralogs. Interestingly, this work not only established similar for three family members neuroblastoma cells, but...
Highlights•The head contains nicastrin ectodomain and overhangs a solute-accessible cavity in base•The base has central channel lateral cleft (putative substrate docking site)•Inhibitors close the rotate head, blocking accessSummaryPresenilin-mediated endoproteolysis of transmembrane proteins plays key role physiological signaling pathogenesis Alzheimer disease some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used...
The amyloid beta (Aβ) peptide is central to the pathogenesis of Alzheimer's disease (AD). Insights into Aβ-interacting proteins are critical for understanding molecular mechanisms underlying Aβ-mediated toxicity. We recently undertook an in-depth in vitro interrogation Aβ1–42 interactome using human frontal lobes as biological source material and taking advantage advances mass spectrometry performance characteristics. These analyses uncovered small cyclic neuropeptide somatostatin (SST) be...
The molecular function of the cellular prion protein (PrPC) and mechanism by which it may contribute to neurotoxicity in diseases Alzheimer's disease are only partially understood. Mouse neuroblastoma Neuro2a cells and, more recently, C2C12 myocytes myotubes have emerged as popular models for investigating biology PrP. epithelial NMuMG might become attractive studying possible involvement PrP a morphogenetic program underlying epithelial-to-mesenchymal transitions. Here we describe...
The amyloid cascade hypothesis posits that the initiating event in Alzheimer's disease (AD) is aggregation and deposition of β-amyloid (Aβ) peptide, which a proteolytic cleavage product precursor protein (APP). Mounting evidence suggests formation spread prion-like Aβ aggregates during AD may contribute to progression. Inoculation transgenic mice overexpress APP with pre-formed results induction cerebral deposition. To determine whether can also be induced when physiological levels are...