Title: Novel and bespoke mouse models for dissecting neurodegenerative disease
Funder: Medical Research Council

Abstract: After finding a novel human mutant gene, usually next is to produce a genetically modified mouse to recapitulate the disease in a tractable experimental system. Mice may not perfectly model human late-onset disorders (such as AD, AD-DS, FTD, ALS), but they are irreplaceable for studying molecular pathology and developing therapies including genetic and stem-cell based treatments. We can also make useful primary cell culture systems from mouse models, as many cell types cannot yet be derived from human iPSCs or embryonic stem cells (ESCs). Current technologies such as the CRISPR/Cas9 system, make it relatively straight-forward to model the majority of human monogenic disorders in mice, and to study likely genetic modifiers by creating the same alleles in mice that are potential disease modulators, as indicated from GWAS studies, in humans1. Thus we have an unprecedented range of mouse models available, including from global collaborations such as the International Knockout Mouse Consortium (IKMC), and we have massive phenotype datasets (for example, from the International Mouse Phenotyping Consortium, IMPC2) that give us unexpected new insights. These resources efficiently increase the pace of biomedical research, but cannot address specific biological questions that require bespoke mouse models. Such models may be challenging, yet feasible, to make, and would be used immediately by neuroscientists, but are difficult to fund because they may be individually expensive to create and fully analyse. Modelling late onset neurodegenerative disease in mice remains challenging. The common neurodegenerative diseases we study are mainly sporadic but between ~10% (for example, ALS, AD) and 40% (FTD) are genetic, usually dominant. Such familial diseases give us a route to understanding sporadic disease, and are modelled by transgenics, generally with a concatamer of transgenes overexpressing a mutant protein from a cDNA under the control of a non-endogenous promoter. The level of mutant protein may correlate with disease severity and the advantage of this type of model is development of pathology within the lifespan of a mouse3. For example, the most widely-used ALS model remains the human mutant SOD1G93A transgenic produced in 19944, which overexpresses human mutant SOD1 protein by up to 24 fold above the endogenous mouse SOD1 protein3, 4. However, transgenics also have phenotypes arising from overexpression per se, as shown when characterising mice that overexpress the wildtype human protein (which may be a valid disease causing mechanism). BAC transgenics are a refinement giving expression from human genomic DNA, usually only 1-3 copies with the endogenous promotor3, 5, and show that complex human splicing patterns, such as that of the Tau protein, can be recreated in mice6. However, the BAC transgenic low ‘dose’ of protein often gives mild phenotypes that mimic only the earliest stages of human neurodegenerative disease and show molecular changes without overt symptoms6; thus although these animals give insight into pathology, they may not be adopted by the community because the mice do not succumb to overt symptoms or endstage disease. More sophisticated ways of working with these mouse models may lead to dissecting early-stage pathology/biomarkers, rather than studying late-stage disease pathways, and even to finding compensatory pathways in mice that may be relevant for human therapeutics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL