Development of a mouse model for Multiple System Atrophy based on peripheral triggers of a-synuclein aggregation and propagation.

Multiple System Atrophy (MSA) is a rare neurodegenerative disease characterized by a rapid and aggressive decline in motor and autonomic functions. Currently there are no symptomatic or disease modifying treatments for MSA patients. The major neuropathological hallmark of these diseases are deposits of alpha synuclein (αSYN ) protein aggregates. The major neuropathological hallmark are alpha-synuclein (αSYN) protein aggregates, which are mostly found as glial cytoplasmic inclusions (GCIs) in oligodendrocytes. Most studies have focused on the central nervous system (CNS), but recent evidence has shown αSYN aggregates in the urinary tract of MSA patients, which correlates with urinary dysfunction being one of the earliest symptoms. αSYN’s ability to propagate like a prion supports the hypothesis that the disease may start in the periphery and later advance to the brain when the motor deficits appear. We hypothesize that peripheral inflammatory insults, such as infections, could act as triggers of MSA in susceptible individuals. To develop disease-modifying therapies for MSA we rely on limited understanding of the disease aetiology. In this project we aim to develop a novel MSA model to study αSYN propagation from the urinary tract to the CNS as a potential contributor to disease pathogenesis. Additionally, we aim to elucidate the role of infections as triggers or modifiers of disease progression. This project will provide new insight into pathogenic mechanisms leading to MSA together with the development of tools that can be used for prospective modelling or therapeutic approaches.