Publication
Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) are neurodegenerative disorders collectively termed synucleinopathies, as they all present proteinaceous pathological aggregates of alpha-synuclein (aSyn) in the brain. Their diagnosis is often challenging, especially in the early phases, as many symptoms overlap. The leading causes are poorly understood and no disease-modifying therapies exist for these diseases. There is an urgent need to deepen our knowledge in the mechanisms driving synucleinopathies, with the ultimate aim of developing reliable diagnostic tools and effective therapies. Cellular and animal models have been proposed to test novel drugs and unravel disease mechanisms, though they are limited in capturing the pathological diversity and complexity that characterize synucleinopathies. Therefore, studies in human tissues remain central to deeply understand morphological alterations as a consequence of aSyn pathology. In this Thesis I aim to provide novel information on the ultrastructure of tissues affected by pathological aggregates, by combining low- and high-resolution imaging methods such as light microscopy and electron microscopy into correlative light and electron microscopy (CLEM). The tissues of choice are both part of central and peripheral nervous systems, respectively brain and skin, as the former is heavily affected during disease, and the latter is an interesting candidate for disease monitoring due its accessibility. Firstly, I contributed to the optimization of a CLEM pipeline suitable for human brain and human skin ultrastructural studies. I later applied this technique to explore aSyn pathological diversity in MSA, uncovering novel pathology in the brain, suggesting an important role in the disease mechanism for MSA. I also investigated the preservation of peripheral myelination in the skin of subjects affected with synucleinopathies and healthy controls, to assess if differences can be potentially used as peripheral biomarkers. Overall, my use of CLEM to study disease pathology of synucleinopathies in human brain and skin has led to novel insights into disease mechanisms, which could contribute to the development of more accurate disease models, and the design of more effective disease modifying therapeutics.