Alpha-synuclein Aggregation in Parkinson's Disease - Is it Relevant and How can we Model it?

Parkinson’s disease (PD) is the second most common neurodegenerative disorder with multiple motor and non-motor symptoms. PD is characterized by the presence on proteinaceous neuronal inclusions (Lewy bodies) which are increasingly observed in multiple brain regions during disease progression. One of the main components in Lewy bodies is misfolded α-synuclein. Studies in animal models and PD patients strongly support α-synuclein contribution in PD progression. Inoculation with extracts from PD patients’ brains induces the development and spread of α-synuclein pathology in rodents, non-human primates, and iPSC-derived human neurons. Thus, α-synuclein has emerged as a promising target for developing disease-modifying therapies, aiming at interfering with initial aggregation by small molecules; enhancing degradation of intracellular α-synuclein by stimulating lysosomal activity; lowering cellular α-synuclein levels by anti-sense oligonucleotides and cell-penetrant nanobodies; inhibiting uptake and targeting transmission of extracellular α-synuclein with active and passive immunization. Pre-formed fibrils (PFFs) able to seed aggregation of endogenous α-synuclein in cultured cells and in vivo have become an essential experimental tool to model and study pathological protein aggregation. PFF model allows investigating the uptake of pathogenic fibrils, their internalization, transport, processing and recruitment of endogenous α-synuclein, formation and maturation of Lewy body-like inclusions and effects of these processes on cell function and survival. With α-synuclein PFFs we can study the mechanism of pathology transmission, motor and behavioral outcomes of accumulation of α-synuclein deposits in different brain structures. While the processes of α-synuclein misfolding and pathology progression are still not fully clear, α-synuclein PFFs have been and will be very instrumental for solving these problems.

Learning Objectives:

1. Define main problems in developing disease-modifying therapies for Parkinson’s disease

2. Identify current therapeutic strategies for Parkinson’s disease treatment

3. Analyze benefits and limitations of modelling alpha-synuclein pathology with pre-formed fibrils