Peter McPherson is a Distinguished James McGill Professor of Neurology and Neurosurgery at the Montreal Neurological Institute of McGill University. He received a Ph.D. in Neuroscience from the University of Iowa working with Dr. Kevin P Campbell and performed post-doctoral training with Dr. Pietro De Camilli at Yale. His laboratory uses biochemical, cell biological, molecular biological and structural approaches to identify and functionally characterize proteins regulating membrane trafficking in the endosomal system. He has published pioneering papers using subcellular proteomics to study the molecular make up of endosomal membranes and has identified numerous links between endocytic membrane trafficking and neurological disease including ataxia, ALS and epileptic encephalopathy. His laboratory has developed approaches for antibody production and validation. Dr. McPherson is a Fellow of the Royal Society of Canada.
The McPherson laboratory uses biochemical, molecular, structural, genetic and cellular approaches to identify and functionally characterize proteins that operate in the formation of clathrin-coated vesicles (CCVs). CCVs are the major vehicles for endocytic uptake of multiple protein and lipid cargo including nutrient and signaling receptors. Following endocytosis, cargo is delivered to endosomes from where it either recycles back to the cell surface or is targeted to lysosomes for degradation. These sorting decisions control the localization and levels of proteins and are altered in cancer and neurological disease. For example, current projects in the lab reveal how disruption in transport of selective cargo from endosomes to the cell surface contributes to the development of glioblastoma and breast cancer.
McPherson's laboratory previously used subcellular proteomics (subcellular fractionation coupled to high throughput mass spectrometry) to identify the full complement of proteins that define CCVs from several tissues. A significant number of the proteins identified were uncharacterized open-reading frames. McPherson's laboratory has characterized the function of a number of these novel proteins although a significant number remain unstudied. One recently identified protein contains a module called a DENN domain. McPherson and his colleagues have demonstrated that DENN domains function enzymatically as guanine-nucleotide exchange factor to activate small GTPase of the Rab family. There are minimally 26 DENN domain proteins in the human genome and an important area of study in the laboratory involves the relationship of these proteins to the ~70 Rabs that function in membrane traffic. One particularly striking example is C9orf72, a DENN domain protein of unknown function. A mutation in C9orf72 is the most common cause of genetic forms of amyotrophic lateral sclerosis (ALS) and the laboratory is working to understand the relationship between endosomal membrane trafficking and disease pathogenesis.
Other proteins identified and or studied in the McPherson laboratory have been linked to other neurological diseases including Huntington disease, autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), and Parkinson disease (PD). For example, we recently demonstrated that the major PD gene LRRK2 binds to clathrin and functions in endosomal membrane trafficking. Moreover, we showed that ARSACS shares pathophysiology with PD. In fact, alterations in the regulation of membrane trafficking is emerging as a central theme in neurodegenerative diseases. Understanding the cell biological basis of neurological disease is a new focus of the laboratory.
Dr Jean-François Trempe obtained a D.Phil. in Biochemistry at the University of Oxford in 2007. His postdoctoral years were spent at McGill University in the department of Biochemistry (2007-2010) and at the Montreal Neurological Institute (2010-2013). He joined McGill’s Department of Pharmacology & Therapeutics in August 2013. He holds a Tier 2 Canada Research Chair in Structural Pharmacology and has received the New Investigator Award from Parkinson Canada in 2014. His goal is to elucidate the function of proteins implicated in Parkinson’s disease through 3D structure determination and proteomics. He has notably solved the structures of Parkin and PINK1, two proteins implicated in a mitochondrial quality control pathway. These structures will pave the way to the development of therapeutics aimed at Parkinson’s disease. Dr Trempe is on the executive committee of the FRQS-funded Centre de Recherche en Biologie Structurale at McGill. Since 2020, he is the Director of the Proteomics platform at the RI-MUHC. His research program is supported by NSERC, CIHR, CFI, the Michael J Fox Foundation and the Agora Trust.
My research interests are in the structure and function of proteins implicated in Parkinson’s disease, Parkin and PINK1 in particular. These proteins have been shown to mediate neuroprotection and mitochondrial maintenance through their enzymatic activities and post-translational modifications (PTMs): Parkin is an E3 ubiquitin ligase and PINK1 is a Ser/Thr kinase. My goals are to: 1) elucidate the composition and 3D structure of molecular complexes formed by Parkin and PINK1 on mitochondria, 2) develop novel therapies for PD based on these structures. My group will use the full range of structural biology tools available at McGill, such as X-ray crystallography, NMR spectroscopy, SAXS, electron microscopy and mass spectrometry, in order to obtain the most complete and highest resolution picture of complexes formed by PINK1 and Parkin. These structures will inform us on how these enzymes become active and modify their substrates, and will guide the development of novel pharmacological targets.
Dr. Edward Fon is a neurologist-scientist at the Montreal Neurological Institute-Hospital (The Neuro) specializing in movement disorders and a Professor in the Department of Neurology and Neurosurgery at McGill University. He is the Director of the FRQS Quebec Parkinson Network (http://rpq-qpn.ca/en/) and the Scientific Director of The Neuro. He was trained at the Université de Montréal, McGill University and the University of California, San Francisco (UCSF). His research focuses on the molecular and cellular events leading to Parkinson's disease (PD). His laboratory has made contributions to understanding the function and cell biology of PD genes and in understanding how defects in these genes lead to PD. In particular, they have focused on understanding the function of Parkin, PINK1, α-synuclein, GBA, LRRK2, TMEM175 and DJ-1. He has established the infrastructure at The Neuro to study these genes and pathways in human patient-derived induced pluripotent stem cells (iPSCs), which they differentiate into neurons, glia and 3D brain organoids. They are currently using these iPSC systems to establish a pipeline to better understand the role of lesser-studied PD genes, identified in recent genome-wide association studies (GWAS), in PD pathogenesis. In addition, he helped establish the Tanenbaum Open Science Institute (TOSI) at The Neuro (https://www.mcgill.ca/neuro/open-science) and oversee its platforms including the Clinical Biological Imaging and Genetic repository (C-BIGr) and iPSC/CRISPR Early Drug Discovery Unit (EDDU).
Dr. Harding is an Assistant Professor in the Faculty of Pharmacy, is a Principal Investigator at the Structural Genomics Consortium and is also cross-appointed to the Department of Pharmacology and Toxicology, all at the University of Toronto. Dr. Harding completed both her undergraduate (MBiochem) and graduate (DPhil) studies at the University of Oxford, the latter training in the lab of Dr. Susan Lea. Dr. Harding moved to the University of Toronto for her postdoctoral training in the lab of Dr. Cheryl Arrowsmith. Dr. Harding was awarded the prestigious Huntington’s Disease Society of America Berman-Topper Family Career Development Fellowship for her research on the structure-function of the Huntington’s disease protein, huntingtin, work that has continued into her independent research career. Her contributions to the field of Huntington’s were further recognised with her award of the 2024 Nancy Wexler Young Investigator Prize, an honour bestowed upon a researcher whose work reflects the highest calibre of excellence, diligence and creative thinking.
Dr. Harding's team uses structural biology, protein biochemistry and chemical biology to study the molecular mechanisms of pathology of repeat expansion disorders, with a primary focus on Huntington’s disease. Huntington’s is a devastating, incurable, genetic, neurodegenerative disease caused by a CAG-tract expansion in the Huntingtin gene. The group is concentrated on three key areas: 1) defining the structure-function relationship of the Huntington’s disease protein, huntingtin, and how this is altered by the disease-causing mutation; 2) molecular mechanisms of repeat expansion disorders like Huntington’s; and 3) development of chemical tools targeting understudied proteins and targets of interest for Huntington’s disease drug discovery.
Dr. Levon Halabelian, PhD is an Assistant Professor at the Department of Pharmacology and Toxicology, UofT, and Principal Investigator in structural biology at the SGC-Toronto. His research focuses on using x-ray crystallography and chemical biology tools to uncover the structures, functions, and therapeutic potential of the human WD-repeat (WDR) domain-containing proteins, one of the largest human protein families and highly enriched in disease-associated proteins. He is involved in structure-guided chemical probes and drug discovery efforts including the novel revolutionary PROTAC drug modality. Many of these projects are in collaboration with the pharmaceutical industry and AI-based drug-discovery groups from academia and industry. Dr. Halabelian is also the interim leader of SGC’s new open science TEP program in Women’s and Children’s Health funded by the Bill & Melinda Gates Foundation.
My group is interested in using the structural and chemical biology tools to uncover the structures and functions of human WD-repeat (WDR) proteins that are often associated with diverse human diseases, including neurodegenerative diseases and cancer. WDR domains comprise an emerging class of druggable protein modules and we seek to develop chemical biology tools to elucidate the function and therapeutic potential of select members of this family, such as LRRK2 and WDR41, which are associated with Parkinson’s disease and amyotrophic-lateral sclerosis (ALS), respectively. We are also interested in targeting key components of the ribosomal biogenesis pathway (WDR12, WDR55) for cancer therapy, which is becoming more attractive as promising findings emerge. Furthermore, many WDRs constitute the substrate recognition domain of E3-ligases, and we are interested in identifying small-molecule handles for the development of proteolysis-targeting chimeras (PROTACs) for targeted protein degradation. My team has also actively contributed to the characterization of other human proteins including DNA-repair proteins (HMCES), tRNA-modifying enzymes (PUS7), protein Arginine methyltransferases (PRMTs) involved in epigenetic regulation and ubiquitin-specific proteases (USP9X).
Dr. Dalia Barsyte-Lovejoy, PhD is an Assistant Professor at the Department of Pharmacology and Toxicology, UofT, and Principal Investigator at the SGC-Toronto, working to understand fundamental regulatory mechanisms of epigenetic proteins and their pharmacological modulation in cancer. The group’s research focuses on disease mechanisms, therapeutic targets, and chemical probe discovery, resulting in over 30 extensively characterized compounds that have helped shape the emerging field of epigenetics and enabled over 50 collaborative projects that are uncovering new epigenetic mechanisms in cancer and its treatment.
We are interested in understanding the mechanism of epigenetic regulators and posttranslational modifications that control cancer cell growth, differentiation, and therapy response. Protein lysine and arginine methyltransferases regulate transcription, genome stability, splicing, RNA metabolism, and other cell processes dictated by which substrates these enzymes methylate. Lysine methyltransferases such as EZH2 and NSD2 primarily methylate histones to establish repressive and active chromatin. In contrast, arginine methyltransferases have a broad scope of substrates ranging from histones to signaling molecules, enzymes, and structural proteins. Epigenetic chromatin regulation, transcriptome, and cellular signaling are fine-tuned by ubiquitin modification. Our work seeks to understand how these posttranslational modifications are misregulated in cancer and identify new therapeutic targets.
Through multidisciplinary research that includes cell and chemical biology, protein structural biology, and many collaborative studies with colleagues across industry and academia, the SGC chemical probes project has generated several probes for methyltransferases, ubiquitin ligases, and deubiquitylases. We are currently using these chemical probes to explore the cellular pathways in poor prognosis acute myeloid leukemia, pancreatic, lung and breast cancer.
Epigenetics and chromatin architecture regulators
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Epigenetics is about how the DNA code is regulated. Proteins that bind/modify DNA and histones play essential roles in cell identity determination, transcription, and genome maintenance. They are often responsible for diseases such as cancer or uncontrolled inflammation. We are studying how epigenetic proteins regulate normal cell processes and how these are subverted in disease. |
Chemical probes as tools for cancer target discovery
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To study epigenetic modifier proteins, we need genetic and pharmacological tools. Chemical probe compounds that potently and selectively inhibit or degrade the target proteins in cells provide tools for modulating activating/repressing histone marks and other cellular signaling pathways. By discovering and using chemical probes, we expand our understanding of the protein function and its therapeutic utility to establish a biological rationale in cancer therapy.
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Link to Open Lab notebooks that features science community posts on our various projects https://openlabnotebooks.org/
Cheryl Arrowsmith is a Senior Scientist at the Princess Margaret Cancer Centre, Professor in the Department of Medical Biophysics, University of Toronto, and the Chief Scientist of the Structural Genomics Consortium (SGC) at the University of Toronto. Her research focuses on the structural and chemical biology of chromatin and epigenetic regulatory factors especially as relates to cancer and drug discovery. In partnership with major pharmaceutical companies, she leads the SGC’s international open science program that is developing and distributing unencumbered Chemical Probes that support the discovery of new medicines. She received her Ph.D. from the University of Toronto and carried out postdoctoral research at Stanford University, and was co-founder of Affinium Pharmaceuticals, which developed a new medicine for multidrug resistant bacteria. She has published over 300 research articles and was recognized by Clarivate Analytics as being among the worlds top 1% of highly cited scientists in 2018, 2019 and 2022. She was elected an AAAS Fellow (2015), and a Fellow of the Royal Society of Canada (2020).
