Initiation and propagation of alpha synuclein oligomers--Relevance for Parkinson s disease

• Applicant: Professorin Dr. Karin Danzer
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 282604822

Parkinsons disease (PD) pathogenesis is characterized by initiation and propagation of alpha synuclein (asyn) pathology. Recent evidence suggests that some forms of asyn are secreted from neurons and taken up by neighboring neurons, thereby suggesting that extracellular asyn species might be toxic in PD. The overall goal of this proposal is to study the underlying mechanism of initiation and propagation of PD pathology based on three lines of investigation. The first approach will study initiation and propagation processes of asyn pathology on the protein level. Here we will investigate cell-to-cell- transmission of asyn oligomers in vitro and in vivo. For this purpose we have generated an innovative animal model based on a split protein complementation assay that allows measurement of asyn oligomers in a highly sensitive way in vivo. In our initial experiments, we found in cell culture that asyn species can form toxic oligomeric species in the extracellular space which are released in association with exosomes or free. We also found that these oligomeric species can be taken up by neurons and act as a nidus for additional oligomer formation. We will now identify the pathologically relevant asyn species responsible for propagation in vitro and in vivo. We will investigate the prion-like transmission of asyn oligomers from neuron to neuron via exosomes and free asyn in vivo. In the second line of investigation we will explore the transmission of asyn oligomers to non-neuronal cells more precisely immune cells. We previously found hyperactive monocytes in the peripheral blood of PD patients but the role of asyn in monocytes activation is not clear yet. We therefore propose to investigate the role of different asyn forms in monocyte activation. We speculate that different extracellular asyn species in free form or associated with exosomes might be an effective trigger for stimulation and/or pre-conditioning of monocytes in the blood of PD patients. As asyn may not be the only transmitting molecular substrate responsible for spreading of disease pathology, we will test in the third line of investigation the hypothesis that transmission of pathology also partially consist of a non-proteinaccious species, e.g. coding or non-coding RNA molecules. We will therefore explore whether coding or non-coding RNA molecules associated to exosomes or free contribute to reprogramming of neighboring cells. Together, in this project we will implement complementary approaches to elucidate the fundamental mechanisms of initiation and propagation of asyn pathology. If this research program will be successful it will directly impact clinical diagnostics in PD and will open new avenues for unique therapeutic interventions for PD and other neurodegenerative diseases.

• DFG Programme: Independent Junior Research Groups