Parkinson’s Research Project Title: Quantitative Mapping of aSyn soluble (monomers, oligomers) and insoluble PTMs in selected brain regions and cell types as a function of disease progression and in familial synucleinopathies

Principal Investigators: Professor Glenda Halliday, Chao Peng & Hilal Lashuel

Institutions: University of Sydney

Study Rationale:

Increasing evidence shows that the pathological hallmarks of Parkinson’s disease, Lewy bodies, and Lewy neurites, are extensively decorated with a large number of chemical modifications on aggregated forms of the presynaptic protein alpha-synuclein (aSyn), which is the primary constituent of these pathological aggregates.  The role of these modifications in regulating the formation of these pathological aggregates, their toxicity, or how they spread in the brain during disease progression remains unknown. Furthermore, very little is known about the relative abundance of the different PTMs in different brain regions and how they change during disease progression.

This research project aims to 1) develop and optimise reproducible protocols for the isolation and handling of aSyn species from human brain tissues while preserving their biochemical diversity [post-translational modifications (PTMs)]; 2) determine the aSyn PTM profile directly in intact tissues in multiple brain regions and different cell types (neurons, astrocytes, and oligodendrocytes) at different stages of disease progression; and 3) determine the PTM profile of alpha-synuclein oligomers in intact brain tissues and after isolation from brain homogenates.

The results obtained from this work will have significant implications for advancing our understanding of which modifications drive neurodegeneration and disease progression and which ones represent cellular mechanisms to protect against these processes. Thus, paving the way for the identification, validation, and prioritisation of novel aSyn species that could have the potential to be used as diagnostic biomarkers for PD or modifications and pathways that could be targeted for developing therapies to treat or slow the progression of PD.