Study Rationale: Inflammation and abnormal protein clumps in the brain are strongly associated with Parkinson's disease (PD). To study the mechanism of inflammation and disease progression related to these protein clumps, a suitable animal model exhibiting these disease phenotypes is essential. The preclinical mouse model of PD induced by alpha-synuclein seeds displays many clinically relevant hallmarks of PD, including dopamine neuron loss, behavioral deficits and widespread alpha-synuclein clumps within the brain. However, the inflammatory phenotype in this model has not been thoroughly characterized. Here, we will characterize the inflammatory phenotype and provide guidelines for establishing consistent phenotypes in this preclinical model of PD.
Hypothesis: We hypothesize that we can identify potential variables that affect the inflammatory phenotype in a preclinical mouse model of PD and use this model to explore additional aspects of inflammatory responses and further validate the observed inflammatory phenotypes.
Study Design: In our initial assessment, we concentrated exclusively on alpha-synuclein clumps and neuroinflammatory phenotypes at a single time point. We have now collected additional biosamples from this preclinical model, including those in the early stage. Using these samples, we will further validate the inflammatory phenotypes and perform multiplex fluorescence imaging analyses to identify specific peripheral immune cells in the vicinity of brain regions that display alpha-synuclein aggregation and inflammatory phenotypes.
Impact on Diagnosis/Treatment of Parkinson’s disease: Validating the inflammatory phenotype in this preclinical model will allow us to use the model to understand the mechanism and effects of inflammation and alpha-synuclein propagation by examining alpha-synuclein pathology and related motor deficits in animals displaying features of PD.
Next Steps for Development: Immunotherapeutic approaches aimed at halting the spread of alpha-synuclein aggregates and inhibiting subsequent neurodegeneration represent a potentially promising therapeutic avenue for PD. This study could help establish a robust phenotype of synuclein pathology and guide the generation of a valid preclinical model for testing therapeutics for PD and Lewy body dementia.