Mansueto, Silvia (2024) Mitochondrial role of α-Synuclein in functional and pathological contexts. [Tesi di dottorato]

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Abstract

α-Synuclein (αS) is an intrinsically disordered protein that plays a central role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies. Its aggregation into amyloid fibrils, which form Lewy bodies, is a hallmark of these neurodegenerative disorders. While αS is primarily known for its involvement in synaptic transmission, growing evidence points to its interaction with mitochondrial membranes and its contribution to mitochondrial dysfunction, a key factor in disease progression. This research explores the structural and functional role of αS in mitochondrial dynamics, with a focus on how its interaction with mitochondrial membranes affects both its normal function and pathological aggregation. Using a combination of biophysical, biochemical, and structural techniques, the study first investigates the membrane-binding properties of wild-type αS through solid-state NMR. It reveals distinct binding modes and conformational changes that vary depending on the lipid environment, highlighting the critical influence of membrane composition on the behaviour of αS. Further analysis evaluates the toxic effects of monomeric and oligomeric αS species on mitochondrial membrane integrity. By investigating key mitochondrial processes—such as maintenance of membrane potential, cytochrome c release, and mitochondrial swelling—the study sheds light on the mitochondrial dysregulation caused by the familial PD-related αSA30P variant. These results highlight the pathological impact of αS aggregation upon interaction with mitochondrial membranes, linking it to the observed mitochondrial dysfunction in PD. Additionally, the study also investigates the kinetics of αS aggregation and the structure of the resulting amyloid fibrils. Using the groundbreaking Cryo-Electron microscopy technique, the study resolves the structure of αSA30P amyloid fibrils formed in the presence of liposomes that mimic the outer mitochondrial membrane. While no new fibril polymorph was identified, the analysis provides valuable insights into how lipids influence the aggregation process, offering a deeper understanding of the molecular mechanisms driving αS aggregation in the presence of biological membranes. In conclusion, this thesis enhances our understanding of the dual role of αS in mitochondrial interactions, illustrating both its physiological membrane-binding properties and its pathological aggregation in toxic species. These findings contribute to a broader understanding of the role of αS in PD pathology and may guide the development of therapeutic strategies aimed at reducing αS toxicity while preserving its normal function in neurons.

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