| dc.description.abstract | Alpha-synuclein aggregation is a hallmark of several neurodegenerative diseases, including Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Misfolded alpha-synuclein proteins form fibrils, which are found in neuronal inclusions alongside membranous organelles. Current models often use alpha-synuclein fibrils as seeds to induce aggregation in cultured neurons. There are various preparation methods for these fibrils, including in vitro-generated fibrils, patient-derived fibrils and in vitro-seeded fibrils. However, the structural diversity and polymorphism of alpha-synuclein fibrils across these models complicate our understanding of their role in neurodegenerative diseases. This review explores studies that have employed cryo-electron microscopy and electron tomography to reveal structural insights.
We found that in vitro-generated fibrils exhibit significant structural polymorphism. Fibrils derived from PD, PDD and DLB are structurally identical, while MSA fibrils show notable differences in their fold. Importantly, patient-derived fibrils contain non-proteinaceous densities, potentially corresponding to cofactors. We observed that both in vitro and seeded fibrils fail to replicate the structures of patient-derived fibrils. Furthermore, in situ studies reveal that there are high densities of alpha-synuclein and organelles present in inclusions, however there is no direct interaction between them. Taken together, studying the molecular progression of alpha-synuclein aggregation in PD remains challenging, emphasizing the need for more accurate models. A deeper understanding of these processes will be critical for the development of targeted therapeutic strategies. | |
