Chairs
Professor Giampietro Schiavo, UCL Institue of Neurology, UK
Professor Giampietro Schiavo, UCL Institue of Neurology, UK
Professor Giampietro Schiavo obtained his PhD from the University of Padua, Italy, and received postdoctoral training at the Department of Biomedical Studies, University of Padua, Italy, and at the Memorial Sloan Kettering Cancer Center in New York, USA, under the supervision of Professors Cesare Montecucco and James Rothman, respectively. He was then recruited as junior group leader at the Cancer Research UK London Research Institute (then Imperial Cancer Research Fund), where he led the Molecular NeuroPathobiology Laboratory until 2013. He then moved to the Institute of Neurology at University College London as a full Professor in 2014. The goal of Professor Schiavo’s research is to understand the mechanisms underlying axonal retrograde transport how neurons control the uptake and sorting of ligands in health and disease conditions.
09:10-09:30
Genomic humanisation and other technologies in mouse
Professor Allan Bradley FRS, The Wellcome Trust Sanger Institute, UK
09:40-10:00
An expanding role for rAAV in complex neurodegenerative mouse modelling
Professor Elizabeth M. Simpson, Centre for Molecular Medicine and Therapeutics (CMMT), University of British Columbia, Canada
Abstract
Neurodegenerative diseases are typically complex; involving both genetic and environmental (including age) factors. This complexity presents a major challenge to the mouse disease-modelling community. Recombinant adeno-associated virus (rAAV) was first discovered in 1965 as a contaminant of simian adenovirus preparations. Since that time, rAAV has been evolved by researchers into a critical tool for transgenesis, applicable to: mouse modelling, mechanistic analyses, and gene therapy. Most recently, three factors have further expanded the applicability of rAAV: 1) relaxation of biohazard regulations enabling the use of rAAV in vitro and in vivo in most research laboratories; 2) isolation, directed evolution, and rationale design of new capsid (protein viral shell) variants that confer novel transduction capabilities to the virus; and 3) implementation of gene regulation by the development of MiniPromoters small enough to fit into the rAAV genome, but still able to provide cell-type restricted expression. For example, a virus that can efficiently cross the blood brain barrier, widely transduce the brain, but only express the transgene in a subset of serotonergic dorsal raphe neurons. With these new viral tools, scientists are combining genetic predisposition with rAAV transgenesis to address question underlying the mechanisms of neurodegeneration, and generate new more complex mouse models.
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Professor Elizabeth M. Simpson, Centre for Molecular Medicine and Therapeutics (CMMT), University of British Columbia, Canada
Professor Elizabeth M. Simpson, Centre for Molecular Medicine and Therapeutics (CMMT), University of British Columbia, Canada
Elizabeth M. Simpson, B.Sc., M.Sc., Ph.D., is a leading scientist in mammalian genetics and genomics. The goal of her research is to improve treatment for human disorders of the brain and eye. Currently, she is focused on the development of gene-based delivery of therapy; also known as “gene therapy”. Dr Simpson has spearheaded multiple large international projects aimed at developing “MiniPromoters”, human DNA control elements that drive gene expression in regions of the brain and eye. The MiniPromoter technology is being used to enable gene therapy for treatment-resistant disorders such as Parkinson disease and Aniridia (congenital blindness).
Dr Simpson is a Senior Scientist at the Centre for Molecular Medicine and Therapeutics (CMMT), a Professor at the University of British Columbia in the Department of Medical Genetics, and an Associate Member in the Departments of Psychiatry and Ophthalmology & Visual Sciences. She also directs the CMMT Mouse Animal Production Service (MAPS).
10:10-10:30
Genome-wide CRISPR knockout screening to study protein quality control and neurodegeneration
Dr Ophir Shalem, University of Pennsylvania and Children's Hospital of Philadelphia, USA
Abstract
The CRISPR associated Cas9 nuclease has emerged as an exciting new tool for genome-wide pooled forward genetic screens. In such experiments, the effect of knockout or activation of thousands of genes, on a specific cellular phenotype, can be measured in single experiments. Cas9 based screens displayed remarkable results including high perturbation efficiency, low off target effects and, most importantly, revealed a large number of previously uncharacterised validated gene hits when compared to previous methods.
Dr Shalem will describe two approaches that are on-going in his lab and how they are using those to study genes that are implicated in neurodegenerative diseases: (1) Using selective vulnerability to identify mediators of protein homeostasis. (2) Combining endogenous gene tagging with fluorescence cell sorting based genome-wide screens to identify upstream regulators of protein expression, protein stability and protein aggregation.
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Dr Ophir Shalem, University of Pennsylvania and Children's Hospital of Philadelphia, USA
Dr Ophir Shalem, University of Pennsylvania and Children's Hospital of Philadelphia, USA
Ophir received a B.Sc. in computer science and computational biology from Beer Sheva University and a Ph.D. from the Weizmann institute of science. He then joined the lab of Professor Feng Zhang for his postdoctoral training where he was one of the pioneers in using CRISPR for genome-wide pooled functional screens. He spent the last year and a half of his postdoc as a visiting scholar in the lab of Andrew Dillin in UC Berkeley developing novel screening paradigms to study protein quality control pathways and neurodegenerative diseases in mammalian cell and animal models. Ophir opened his own lab at the University of Pennsylvania in September 2016 where he is continuing to use functional genomics approaches to study neurodegeneration.
11:20-11:40
APP-overexpressing mice versus App knock-in mice for the preclinical studies of Alzheimer’s disease
Professor Takaomi Saido , RIKEN Brain Science Institute, Japan
Abstract
Animal models of human diseases that recapitulate their pathology in an accurate manner represent indispensable tools for understanding molecular mechanisms and for use in preclinical studies. For more than two decades, the Alzheimer’s disease (AD) research community has depended on transgenic (Tg) mouse models that overexpress mutant amyloid precursor protein (APP) or APP and presenilin (PS), mutations of which cause familial AD (FAD). These mice exhibit the pathological hallmarks of AD, but it is becoming clear that the overexpression of transgenes from artificial promotors may cause phenotypes that may not related to AD. The next-generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene, leading to A accumulation without overexpression of APP or PS, avoiding at least these problems. Professor Saido will describe the different mouse models used to study AD including benefits and potential pitfalls. Professor Saido will then propose the broad adaptation of these models and the use of similar strategies to generate additional models for other neurodegenerative disorders.
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Professor Takaomi Saido , RIKEN Brain Science Institute, Japan
Professor Takaomi Saido , RIKEN Brain Science Institute, Japan
Takaomi C. Saido (TCS) is a Senior Team Leader, Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute. He received a PhD from Graduate School of Pharmaceutical Science, University of Tokyo, in 1988 and then became a Research Scientist at Tokyo Metropolitan Institute of Medical Science, where he mainly worked on the pathophysiology of calpain and on the pathological biochemistry of Alzheimer’s disease. After moving to RIKEN in 1997, he has continued to work both on calpain and Alzheimer’s disease. TCS identified the major A-degrading enzyme, neprilysin (Nat Med, 2000; Science, 2001; Lancet, 2003), and created the next-generation mouse models of Alzheimer’s disease (Nat Neurosci, 2014; J Neurosci, 2016). The calpastatin (CAST) knockout, conventional/conditional calpain 2 (CAPN2) knockout and single App knock-in mice generated in his laboratory are widely used in the research community.
11:50-12:10
Working with complex mouse models to understand neurodegenerative disease
Dr Frances Wiseman, UCL Institute of Neurology, UK
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Dr Frances Wiseman, UCL Institute of Neurology, UK
Dr Frances Wiseman, UCL Institute of Neurology, UK
Frances K. Wiseman was an undergraduate at the University of Oxford, UK, and completed her masters and Ph.D. at the University of Edinburgh, UK. Since 2007, she has been based at the Institute of Neurology, University College London, UK, studying the mechanisms that underlie the development of Alzheimer disease in people with Down syndrome.
12:20-12:40
Improving validity of disease models through phenotype-driven approaches and changing genetic background
Dr Robert W. Burgess, The Jackson Laboratory, Bar Harbor, Maine, USA
Abstract
Precise genetic engineering of human disease-associated mutations into model organisms may not result in precise reproduction of the disease phenotype. This represents a conflict between face validity (does the model look right), and construct validity (does the phenotype develop for the right reason). The ultimate goal of a model is predictive validity (whether what we learn from the model translates to humans); however, the model’s acceptance will be greatest when face validity and construct validity align. Why an engineered model does not recapitulate the human disease phenotype is often unclear; however, these goals can sometimes be better aligned. First, phenotype-driven approaches to developing models start with good face validity, by definition. Such mutations have led to the identification of new human disease genes, or the identification of model-specific alleles with better face validity than precision engineered alleles. Second, genetic background almost invariably alters the phenotype in model organisms and in humans, resulting in variable severity, partial penetrance, and differing responses to treatment. We cannot always predict a sensitive or resistant strain background, but studying a given mutation on a variety of backgrounds can result in improved models. Furthermore, modifier loci can inform our understanding of disease mechanisms and therapeutic options.
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Dr Robert W. Burgess, The Jackson Laboratory, Bar Harbor, Maine, USA
Dr Robert W. Burgess, The Jackson Laboratory, Bar Harbor, Maine, USA
Dr Burgess received his B.S. In Biochemistry and Physiology from Michigan State University, and his Ph.D. In Neuroscience from Stanford University. Following postdoctoral training at Washington University, St. Louis, Dr Burgess joined the faculty of The Jackson Laboratory in 2001. The Burgess lab seeks to understand the molecular mechanisms of synapse formation and maintenance at two sites in the nervous system: the peripheral neuromuscular junction and the retina. In all of these studies, we are addressing basic molecular mechanisms, but these basic mechanisms have relevance to human neuromuscular and neurodevelopmental disorders. Our continued research on the genetics underlying these disorders, and our continuing effort to identify new genes involved in these processes, will increase our understanding of the molecules required to form and maintain synaptic connectivity in the nervous system.
12:50-13:00
Discussion: Tissue specificity, site of onset, time of onset, gain or loss of function
Professor Giampietro Schiavo, UCL Institue of Neurology, UK
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Professor Giampietro Schiavo, UCL Institue of Neurology, UK
Professor Giampietro Schiavo, UCL Institue of Neurology, UK
Professor Giampietro Schiavo obtained his PhD from the University of Padua, Italy, and received postdoctoral training at the Department of Biomedical Studies, University of Padua, Italy, and at the Memorial Sloan Kettering Cancer Center in New York, USA, under the supervision of Professors Cesare Montecucco and James Rothman, respectively. He was then recruited as junior group leader at the Cancer Research UK London Research Institute (then Imperial Cancer Research Fund), where he led the Molecular NeuroPathobiology Laboratory until 2013. He then moved to the Institute of Neurology at University College London as a full Professor in 2014. The goal of Professor Schiavo’s research is to understand the mechanisms underlying axonal retrograde transport how neurons control the uptake and sorting of ligands in health and disease conditions.