Evaluation of synuclein Parkinson's disease model in transgenic mice Renee C. Gentzel1*, Sarah Jinn1, Dawn Toolan1, Joel Schachter1, Sean M. Smith1, Jacob Marcus1 1Neuroscience Discovery, Merck Research Laboratories, West Point, PA 19486 *Corresponding Author
Parkinson's disease (PD) pathology is predominated by aberrant forms of alpha-synuclein protein (aSyn). Transmission of this misfolded, aggregated aSyn is thought to occur during the progression of PD, and this hypothesis is supported by current animal models which incorporate intracranial administration of recombinant sonicated aSyn fibrils (aSyn PFFs). We have reproduced this animal model in our laboratories, confirming that injection of aSyn PFFs into wild-type (WT) rodent striatum results in the formation and spread of synuclein pathology to anatomically interconnected brain regions, mimicking the human disease. We next investigated the interplay between genetic risk factors for PD and this PFF model through the use of genetically modified mouse models. Mutations of the synuclein gene itself can increase risk for PD, as do mutations to beta-glucocerebrosidase (GBA), an enzyme involved in glycolipid metabolism. We injected PFFs into a mice expressing A30P mutant human synuclein or to mice with D409V GBA mutation reflecting these two types of mutations that increase PD risk. In each case, induced aSyn pathology was compared to age-matched WT mice. The results of these experiments have helped us to understand the biology behind PD and how to best utilize this type of PFF model for drug discovery research.