From the heterologous cross-seeding of amyloid aggregation to explore the early triggering factors and pathogenic mechanisms of Parkinson´s disease and related disorders

Abnormal accumulation and aggregation of misfolded α-synuclein (α-syn) are the key pathological processes of Parkinson’s disease (PD), however, it is still unclear how, where and what triggers α-syn aggregation.

Our recent studies show that diabetes related Islet amyloid polypeptide (IAPP), bacterial infection related amyloid protein phenol soluble modulins α (PSMα) and aggregated Tau can facilitate α-syn aggregation.

Here, we hypothesize that the “heterologous amyloid protein cross-seeding” can induce α-syn nucleation and aggregation at the initial phase of PD.

Using cell-free, cell and animal models, we will employ interdisciplinary methods of biochemistry, molecular biology and biophysical imaging (Soft X-ray spectromicroscopy and label-free optical photothermal infrared super resolution microspectroscopy) to reveal the triggering factors and mechanisms of heterologous amyloid protein cross-seeded α-syn aggregation.

Specifically, we have selected three groups of amyloid proteins from three common systemic diseases, namely IAPP (diabetes), Tau (0N3R and 2N4R) (tauopathy) and PSMα (S. Aureus infection) as seeding proteins for α-syn nucleation and aggregation.

We will study the cross-seeded α-syn, and determine the biophysical and molecular properties, together with their cytotoxicity and spreading potency.

This project designates to reveal the initiation mechanisms of α-syn pathology and hopefully provide a basis for PD clinical diagnostic and therapeutic researches.