DEVELOPMENT AND OPTIMALISATION OF AN ALPHA-SYNUCLEIN-BASED CELLULAR AND MOUSE MODEL FOR PARKINSON’S DISEASE

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder that affects 6 to 10 million people worldwide. The neuropathological hallmarks are a progressive degeneration of dopaminergic (DA) neurons of the substantia nigra (SN) pars compacta and eosinophilic cytoplasmic inclusions called Lewy bodies (LBs) and Lewy neurites. α-synuclein (αSYN) is a known key player, but the exact role of αSYN aggregation in the pathogenesis of PD remains incompletely understood. The first goal of this project is to develop and validate an αSYN-based humanized mouse model for PD that reproduces key features of this disease including accumulation of LB inclusions, spreading of αSYN pathology throughout the brain, progressive loss of DA neurons in the SN and development of motor function deficits with age. This will allow us to study the seed and spread of αSYN pathology and perform in vivo drug discovery and testing. The second objective of this project is to create an in vitro PD model based on seeding with recombinant αSYN preformed fibrils. However, in order to increase the translational value, we aim to develop a human iPSC-based assay for αSYN aggregation. By creating these disease models, this project will contribute to future discovery and development of novel therapeutic strategies that can cure the disease or slow down its progression.