Skip to content
What's on

Meeting the challenges of modelling neurodegenerative disease in mice

Scientific meeting

Location

Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ

Overview

Theo Murphy international scientific meeting organised by Professor Elizabeth Fisher, Professor Giampietro Schiavo and Dr Pietro Fratta

Neuromuscular junction and vascular plexus. Copyright James Sleigh, UCL Institute of Neurology

New technologies for engineering the mouse genome are increasingly sophisticated. However, mouse models of neurodegeneration try to recapitulate human late-onset disorders in an animal that lives for two years and has important differences in physiology and biochemistry. How can we best model neurodegeneration? What features matter? What has given us most insight? What is the future we would like?

The schedule of talks and speaker biographies will shortly be available below. A draft programme is available to download.

Recorded audio of the presentations will be available on this page after the meeting has taken place.

Attending this event

  • Free to attend
  • Advanced registration essential (please request an invite)
  • Catering and accommodation available to purchase during registration

Enquires: Contact the Scientific Programmes team

Event organisers

Select an organiser for more information

Schedule of talks

26 June

09:00-13:00

Using new technologies to model key questions in neurodegeneration

7 talks Show detail Hide detail

Chairs

Professor Giampietro Schiavo, UCL Institue of Neurology, UK

09:10-09:30 Genomic humanisation and other technologies in mouse

Professor Allan Bradley FRS, The Wellcome Trust Sanger Institute, UK

Show speakers

09:30-09:40 Discussion

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.

Show speakers

10:00-10:10 Discussion

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. 


Show speakers

10:30-10:40 Discussion

10:40-11:20 Coffee

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.

Show speakers

11:40-11:50 Discussion

11:50-12:10 Working with complex mouse models to understand neurodegenerative disease

Dr Frances Wiseman, UCL Institute of Neurology, UK

Show speakers

12:10-12:20 Discussion

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.

Show speakers

12:40-12:50 Discussion

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

Show speakers

13:00-14:00

Lunch

14:00-17:00

Understanding and exploiting? – differences in mouse and human

6 talks Show detail Hide detail

Chairs

Dr Pietro Fratta, UCL Institute of Neurology, UK

14:00-14:20 Mouse physiology in modelling neurodegenerative disorders

Professor Linda Greensmith , UCL Institute of Neurology, UK

Show speakers

14:20-14:30 Discussion

14:30-14:50 Understanding neuropathology in neurodegeneration models aligning human and mouse

Professor Maria Grazia Spillantini, University of Cambridge, UK

Show speakers

14:50-15:00 Discussion

15:00-15:40 Tea

15:40-16:00 Mapping and manipulating neural circuits in vivo, possible applications in neurodegeneration models

Dr Marco Tripodi, MRC Laboratory of Molecular Biology, Cambridge, UK

Abstract

Neural networks are emerging as the fundamental computational unit of the brain and it is becoming progressively clearer that network dysfunction is at the core of a number of psychiatric and neurodegenerative disorders. Yet, our ability to target specific networks for functional or genetic manipulations remains limited. Monosynaptically restricted Rabies virus facilitates the anatomical investigation of neural circuits. However, the inherent cytotoxicity of the Rabies largely prevents its implementation in long-term functional studies and for the genetic manipulation of neural networks. To overcome this limitation, we developed a Self-inactivating ΔG-Rabies virus (SiR) that transcriptionally disappears from the infected neurons while leaving permanent genetic access to the traced network. SiR provides a virtually unlimited temporal window for the genetic and functional manipulation of neural circuits in vivo without adverse effects on neuronal physiology and circuit function.

Show speakers

16:00-16:10 Discussion

16:10-16:30 Neuroimaging of mouse models

Professor Mark Lythgoe , UCL Centre for Advanced Biomedical Imaging, UK

Abstract

Imaging has revolutionised biomedical research over the past four decades, and innovations are continuing at an increasing pace. The immense challenge of annotating the entire mouse genome has led to the development of cutting-edge imaging tools in a drive to discover novel structural and functional information with a particular relevance to human pathobiology. Furthermore, sophisticated computational techniques are being combined with novel data acquisition for a deeper understanding of biological processes. This talk will include the latest neuroimaging developments, across a range of scales, in cellular and functional imaging using high-field MRI, Optical and Photoacoustic Imaging. I will introduce experimental optical techniques to image genes and function in mouse studies. As well as the development of new MRI methods to image glymphatic function, probe tissue microstructure, together with methods to image and guide therapies in vivo.

Show speakers

16:30-16:40 Discussion

16:40-17:00 Discussion: Differences in mouse versus humans, are we simply modelling mouse neurodegeneration?

Dr Pietro Fratta, UCL Institute of Neurology, UK

Show speakers

27 June

09:00-12:30

What do we want from disease models?

6 talks Show detail Hide detail

Chairs

Professor Elizabeth Fisher, UCL Institute of Neurology, UK

09:15-09:35 Molecular mechanisms of neurodegeneration - insights from cellular and in vitro models

Dr Dorothee Dormann, Ludwig-Maximilians-University Munich, Germany

Abstract

Pathological protein aggregates are a central hallmark of all neurodegenerative diseases. In the related disorders ALS and FTD, the pathological aggregates consist mostly of the ubiquitous RNA-binding proteins TDP-43 or FUS. Both proteins are usually located in the nucleus, whereas in neurons and glial cells of ALS/FTD patients, they are partially lost from the nucleus and accumulate in large cytoplasmic inclusions. How TDP-43 mislocalization and aggregation arises in ALS/FTD patients is largely unclear. For FUS, we have successfully used cellular and in vitro models combined with neuropathological analysis of human post-mortem brains to identify two key pathomechanisms that appear to cause FUS mislocalization and aggregation in ALS or FTD patients: (1) In ALS-FUS, genetic mutations in the nuclear localization signal (NLS) of FUS cause impaired nuclear import of FUS, thus causing reduced nuclear and increased cytoplasmic FUS levels. This has recently been modelled in mice and was shown to cause age-dependent motor neuron degeneration1-3. However, no cytosolic FUS aggregates are found in these mice, suggesting that additional pathological hits / defects may be necessary to cause FUS aggregation in vivo. (2) In FTD-FUS patients the nuclear import receptor of FUS, Transportin, is aggregated and a post-translational modification of FUS, arginine methylation, is lost. Our recent in vitro work has shown that both defects promote pathological phase transitions and aggregation of FUS. The next challenge will be to model these defects in mice, in order to test whether they indeed cause FUS pathology and neurodegeneration in vivo.

Show speakers

09:35-09:45 Discussion

09:45-10:05 Better modelling of human disease progression in mouse models - rationale and insights to be gained

Professor Karen Duff, Columbia University Medical Center, New York, USA

Show speakers

10:05-10:15 Discussion

10:15-10:35 Insights into the molecular basis of Huntington’s disease

Professor Gillian Bates, UCL Institute of Neurology, UK

Abstract

Huntington’s disease (HD) is caused by a CAG/polyglutamine repeat expansion. HD research benefits from the availability of a wide-range of complementary mouse lines that model of aspects of the disease and have been validated in that they have predicted the presence of specific pathogenic processes in HD patients e.g. HTT aggregation and transcriptional dysregulation. HD mouse models are particularly useful for uncovering pathogenic mechanisms that lie proximal to the mutation. The group works with two versions of HD mice, those that are transgenic for a 5’ genomic fragment of HTT incorporating exon 1 (R6 lines), and with a range of knock-in models in which a CAG expansion has been inserted into mouse Htt. The molecular, behavioural, physiological and histological phenotypes of these two very different types of model are strikingly similar in symptomatic mice. This led us to discover that in all knock-in models, exon 1 does not always splice to exon 2 resulting in the presence of a small polyadenylated HTT mRNA that encodes the highly pathogenic exon 1 HTT protein. The R6 mouse lines are therefore a model of this incomplete splicing event, which has been subsequently shown to occur in HD patient post-mortem brain samples.    


Show speakers

10:35-10:45 Discussion

10:45-11:15 Coffee

11:15-11:35 Lost in translation: why do rodent models fail?

Professor David Bannerman, University of Oxford, UK

Abstract

Rodent models of neuropsychiatric and neurodegenerative disorders are important experimental tools but their utility is often questioned. One area of particular concern is at the level of behavioural phenotyping. A key question is whether we are even studying the same psychological process(es) in rodents and humans, supported by the same neural circuits and structures. Memory impairment is a primary feature of many brain disorders and diseases, and is commonly assessed in rodent models using a wide variety of tasks. Many of the commonly used assays (e.g. watermaze, contextual fear, novel object recognition) are quick and easy to perform, but deficits are prone to misinterpretation and may not model the intended human phenotype. This will be illustrated with behavioural data from various mouse models of impaired neuroplasticity and calls for a more rigorous assessment of behavioural phenotypes in which psychological processes are identified across batteries of tests. Furthermore, I will describe a novel technique, tissue oxygen voltammetry (TOV) which measures the concentration of tissue oxygen in a given brain region in freely moving, behaving animals, and thus provides a haemodynamic signal of neural activity which is broadly analogous to the BOLD signal used in fMRI. TOV therefore represents an important approach for translating between rodent studies and humans in terms of identifying relevant neural circuits across species.

Show speakers

11:35-11:45 Discussion

11:45-12:05 Aligning mouse and human behaviours in neurodegeneration

Professor Mark Good, Cardiff University, UK

Abstract

Disruption to episodic memory is a major feature of the early stages of Alzheimer’s disease.  Due to its historical association with episodic memory deficits in humans, the assessment of animal models of dementia has been largely hippocampus-centric. The use of ‘hippocampus-dependent’ tasks is common and assumes that this structure is central to memory dysfunction and that we fully understand its normal contribution to cognition. This is clearly not the case. Functional MRI imaging studies in human patients and those carrying risk genes for dementia, point to disruption not of an individual brain structure but of integrated networks that support memory – indeed some network changes may be present prior to manifestation of the clinical disease. A ‘one-structure’ approach to the assessment of animal models under estimates the impact of pathology and risk genes on the brain and it also restricts evaluation of potential therapies. In order to understand how ageing, genetic risk factors and core pathological changes eventually lead to progressive cognitive decline, an approach that focuses on the activity of integrated networks common to tasks in human and animals, may be very valuable. Such a strategy would promote harmonization of cognitive testing in rodents and humans and, ceteris paribus, enhance the translation of therapies.

Show speakers

12:05-12:15 Discussion

12:15-12:30 Discussion: Transgenics or knock ins? Mouse paradigms or translating into human studies?

Professor Elizabeth Fisher, UCL Institute of Neurology, UK

Show speakers

12:30-13:30

Lunch

13:30-17:00

Optimising future research

6 talks Show detail Hide detail

Chairs

Dr Pietro Fratta, UCL Institute of Neurology, UK

13:30-13:50 The mouse toolbox we need for neurodegeneration - lessons from prion diseases

Professor John Collinge FRS, UCL Institute of Neurology, UK

Show speakers

13:50-14:00 Discussion

14:00-14:20 What biopharma needs, what we do right and what we do wrong

Dr Eric Karran, Foundational Neuroscience Center, Cambridge, Massachusetts, USA

Abstract

The biopharma industry is in a unique position in the provision of healthcare.  On the one hand, it can point to a range of stunning successes: very effective therapies for HIV, HCV, a pharmacological armamentarium trained against hypertension, diabetes and hypercholersterolaemia; personalized approaches for some tumours.  On the other hand, a lack of success in providing true disease modifying therapeutics for Alzheimer’s disease and Parkinson’s disease. Dr Karran will examine those areas of scientific and operational strength that exist in pharma, and highlight some areas for future growth and development.

Show speakers

14:20-14:30 Discussion

14:30-15:00 Tea

15:00-15:20 Aiming for validity and reproducibility in mouse models of neurodegenerative disease

Professor Monica Justice, SickKids, Toronto, Canada

Abstract

Pre-clinical studies using the mouse as a model for human disease have been criticized due to the failure of data to be replicated or to translate to the human. Common sources of error include bias in data analysis and reporting, as well as a failure to accurately report experimental conditions and controls. Neurodegenerative diseases present unique problems in disease modeling, perhaps because the lifespan of a mouse does not mimic that of a human. Overall, evidence that the mouse is a valid and predictive model of the human, and that the intervention targets similar molecules must be obtained prior to pre-clinical studies. Therefore, biomarkers and predictive assessments must be stringently defined. I will discuss model validity, predictive measurements, sources of experimental variation and their influence on phenotypic outcome using a mouse model for Rett syndrome as an archetype for preclinical studies. Here, understanding the differences presented by the animal model could be informative to human precision medicine. Therefore, perhaps the ultimate goal should not be to mimic the disease entirely as it presents in the human, but to aim to reveal mechanism, thereby informing disease and its treatment.

Show speakers

15:20-15:30 Discussion

15:30-16:50 Modifier genes of neurodegeneration – a means to mechanism and new biology

Professor Susan Ackerman, University of California, USA

Abstract

To identify the underlying molecular causes of neurodegeneration, Professor Ackerman’s lab uses a forward genetic approach in mice. Importantly, this phenotype-driven approach allows the identification, without a priori assumptions, of molecules critical to these processes. However, the specific role of these molecules in neuronal homeostasis can be difficult to ascertain, particularly for molecules without defined function. To enable the definition of the biological pathways that when disrupted by mutations result in neurodegeneration, the lab has utilised forward genetics to identify modifier genes. In brief, the group analyses the consequences of alleles of various inbred mouse strains to identify genes which alter neuron death mediated by chemically-induced or spontaneous mutations. These modifier genes and the accompanying biochemical and genomic studies have helped pinpoint novel pathways involved in neuronal homeostasis in the ageing brain.

Show speakers

15:50-16:00 Discussion

16:00-16:20 Hallmarks of Alzheimer’s disease in stem cell-derived human neurons transplanted into mouse brain

Professor Bart De Strooper, UK Dementia Research Institute, University College London, VIB and KU Leuven Belgium

Abstract

Human pluripotent stem cells (PSC) provide a unique entry to study species-specific aspects of human disorders such as Alzheimer’s disease (AD). However in vitro culture of neurons deprives them of their natural environment. Here we transplanted human PSC-derived cortical neuronal precursors into the brain of a murine AD model. Human neurons differentiate and integrate into the brain, express 3R/4R Tau splice forms, show abnormal phosphorylation and conformational Tau changes and undergo neurodegeneration. Remarkably, cell death was dissociated from tangle formation in this natural 3D model of AD. Using genome wide expression analysis, we observed up-regulation of genes involved in myelination and down-regulation of genes related to memory and cognition, synaptic transmission and neuron projection. This novel chimeric model for AD displays human-specific pathological features and allows the analysis of different genetic backgrounds and mutations during the course of the disease.

Show speakers

16:20-16:30 Discussion

16:30-17:00 Discussion: Differences in mouse versus humans, are we simply modelling mouse neurodegeneration?

Professor Giampietro Schiavo, UCL Institue of Neurology, UK
Professor Elizabeth Fisher, UCL Institute of Neurology, UK
Dr Pietro Fratta, UCL Institute of Neurology, UK

Show speakers
Meeting the challenges of modelling neurodegenerative disease in mice Kavli Royal Society Centre, Chicheley Hall Newport Pagnell Buckinghamshire MK16 9JJ