Spatiotemporal transcriptome and proteome analysis of α-Synuclein pathology in Parkinson’s disease: Identification of cell type-specific vulnerability and tolerance mechanisms

α-Synuclein (α-Syn) pathology is inextricably linked to the pathogenesis of Parkinson’s disease (PD), yet we have very limited understanding why specific neuronal populations are vulnerable in PD while others are much more resistant.

Likewise, we have very limited knowledge how neurons transit from a resistant state to a vulnerable state, how this transition is linked to distinct stages of α-Syn pathology, and how other cells contribute to these processes.

We will perform an unprecedented, integrated, spatiotemporal transcriptome and proteome analysis of neuronal and non-neuronal responses to α-Syn pathology.

We will create a 4D dynamic cell atlas of the distribution of specific subpopulations and their transcriptome/proteome changes in vulnerable and nonvulnerable brain regions, and characterise the spatial cellular landscape in relation to α-Syn pathology.

Integrative bioinformatics analyses, including network modelling and master regulator analyses, will identify biomarkers,pathways, and signatures in cellular sub-types susceptible and resistant to α-Syn pathology that may precede appearance of the pathological phenotype.

Utilising systems biology approaches such as genome scale modelling, previously identified disease pathways will be systematically investigated in the context of disease progression and the cell types in which they occur, and mapped to master regulators.