The SYNERGY mouse: a bi-genic synucleinopathy model
Ottawa Hospital Research Institute, University of Ottawa, College of Medicine and Health Sciences
Dementia with Lewy bodies (DLB) and Parkinson disease (PD) are related, progressive neurodegenerative disorders that remain incurable due in part to the lack of adequate animal models that are essential in drug development. In an effort to restage PD and DLB and their course in mice, we have created a bi-genic mouse model that combines the complex genetics of these two human disorders and captures a key pathophysiological aspect that underlies their development. SYNERGY mice carry two of the most relevant genetic risk factors to developing PD and DLB in humans: expression of mutant acid-betaglucocerebrosidase (Gba1) protein and elevation in human alpha-synuclein (SNCA) load.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
Animal models are critical to preclinical drug development. We believe that owing to their ‘complex genetic’ design SYNERGY mice represent the most relevant DLB/PD model created to date to facilitate translational research: they serve as a laboratory tool to better study the evolution of behavioral, biochemical and pathological changes which underlie neurodegeneration in humans, and will thus facilitate drug screening and testing for future therapy of DLB and PD that is cause-directed.
Based on our early results and together with the careful analysis of the parental strains, we anticipate that SYNERGY mice will develop age-dependent deficits in odour processing, motor performance and cognitive function. These behavioural changes will be examined in the context of misprocessing of alpha-synuclein and changes in certain brain lipids. Our proposed studies will address an important first stage of model validation, namely to establish how age-dependent changes in mouse behaviour relate to biochemical alterations leading to microscopically detectable pathology. Moreover, the results from this effort will inform the second phase of model validation, namely to provide proof-of-concept that SYNERGY mice can also serve as a valuable and versatile platform for carrying out drug discovery and validation as well as biomarker initiatives. This second phase is outlined in a separate proposal.
Mutations in the GBA1 gene and dysregulation of α-synuclein are key risk factors for Parkinson disease and dementia with Lewy bodies, two closely related neurodegenerative disorders. Both represent leading candidate drug targets for future therapy. A roadblock in therapeutic advancement has been the lack of adequate animal models for preclinical studies. We have created a new mouse model, called the SYNERGY mouse, which combines both genetic risk factors: mutations in the murine Gba1 gene and over-expression mutant human α-synuclein. We predicted that this mouse would develop key aspects of the human disease and that this would worsen as they age. Specifically we predicted that the mice would develop motor and cognitive impairments and that these deficits would correlate with altered α-synuclein expression and Gba1-linked changes in the lipid profile of the brain. With the support of the Weston Brain Institute, we characterized the mice at three ages: young (3 months old), mid (6 months old) and older (12 months old). Excitingly, we found that compared to mice that express normal Gba1 and normal mouse α-synuclein, the SYNERGY mice performed worse on challenging motor tasks as young as 3 months of age that worsened as they aged. They also showed impaired cognitive function by 6 months of age. Interestingly, these changes were dependent on the presence of human α-synuclein expression, but were not made worse by the additional mutations in Gba1 at the ages tested. We did, however, observe that the mutations in Gba1 caused a rise in the accumulation of α-synuclein in the brains of these mice (and altered lipid profiles), suggesting that the further accumulation of α-synuclein downstream of mutant Gba1 alleles in itself is not sufficient to cause significant changes in the behavioural outcomes tested, at the ages tested. Further studies at the protein, lipid and brain cell level will provide important insight into the pathways that lead to brain cell loss in these two related neurodegenerative diseases and will ultimately help inform clinical trials and accelerate drug discovery.