Role of Neuroinflammation in Parkinson's Disease and Related Disorders

Abstract: Synucleinopathies are neurodegenerative disorders characterized by intracellular protein aggregates, progressive neurodegeneration, and neuroinflammation. Alpha-synuclein (a-syn) is the principal component of intracellular aggregates and can be modified by several mutations and post-translational modifications (PTMs), which can alter the protein structure affecting its aggregation, toxicity, and ability to spread.Microglia and astrocyte cells are important cells for the immuno defense within the brain. Although these cell populations are distributed in all brain parenchyma, their density, morphology, and transcriptomes are variable. Whether and how these differences could lead to different inflammatory responses in several brain regions are not well understood.Studies demonstrated that a-syn oligomers or aggregates could trigger microglial and astrocytic activation. In contrast, other authors showed that some a-syn PTMs could derive from an inflammatory condition. These findings suggest the presence of mutual relations between a-syn and the inflammatory system, which could affect the course of these pathologies. While several studies concentrated on the ability of a- syn species to induce an inflammatory response, a few were dedicated to the impact of neuroinflammation on a-syn pathology.This thesis aimed to explore the role of neuroinflammation in synucleinopathies in relation to a-syn pathology and to dopaminergic synaptic loss and neurodegeneration. Firstly, we generated a microglial-like cell model that stably expressed a-syn. Using this model, we investigated a-syn PTMs induced by these cells, their ability to develop aggregates, and their toxicity. Then, we performed a high-throughput screening using a FRET-based system. We identified three compounds that interfere with the a-syn aggregation process in HEK 293T cell line over-expressing a-syn. Subsequently, we investigated whether the inflammatory response within the brain was different in several brain regions. We observed heterogeneity for several parameters and a peculiar inflammatory activation in the substantia nigra (SN). In the end, we investigated a-syn conformations in different human brain regions and synucleinopathies. We found different conformations and identified an a-syn truncation that is more common in Parkinson ́s disease than dementia with Lewy bodies and multiple system atrophy. Our studies indicated that inflammation could have an impact on neurodegeneration in SN and on a-syn processing.