Unraveling the role of the immune system in alpha-synuclein spreading and neurotoxicity in vivo.

Misfolded protein aggregates appear to be a common feature of several ageing-related neurodegenerative diseases. Evidence is emerging that these protein aggregates can adopt distinct conformations with differences in their structural and phenotypic traits. The discovery of the prion-like transmissible nature of these proteins suggests a pathogenic trigger which might propagate throughout the nervous system driving the progression of the disease. However, several crucial questions about the mechanism and relevance for human disease remain unanswered. In addition, there is mounting evidence that neuroinflammatory processes are closely linked to neurodegeneration during ageing. In this project I aim to investigate how different alpha-synuclein (aSYN) assemblies are linked to neuroinflammation, spreading of neuropathology and neurodegeneration in Parkinson’s disease. First I will compare the structural, seeding and spreading properties of recombinant and patient-derived aSYN assemblies in the rat brain to bridge the gap between our animal model work and human pathology, ensuring the translational nature of our proposal. Next, I want to gain insight into the involvement of the immune system in aSYN spreading and neurotoxicity. The strength and innovative nature of this project lies in the first exploration of a link between distinct aSYN assemblies, spreading of neuropathology and neuroinflammation.