Modeling initiation, progression and spreading of Parkinson´s disease pathology and its use for the exploration of novel disease-modifying therapies

The project aims to explore a novel approach to modeling of the disease process seen in Parkinson´s disease based on AAV-mediated overexpression of human α-synuclein in combination with delivery preformed human α-synuclein fibrils, which are known to act as seeds for the development of Lewy-like inclusions and aggregates in the affected dopamine neurons.

The progressive and accelerated synucleinopathy triggered by this combined approach reproduces the cardinal features of the human disease, including Lewy-like synucleinopathy, neuroinflammation, and progressive dopaminergic cell loss. We will use this new model to explore the role of endoplasmatic reticulum (ER) stress as a trigger of α-synuclein pathology and cell death in nigral dopamine neurons, and study the ability of a new class of ER-stress modulators, CDNF and MANF, to block the disease process in this model. In addition, we will perform experiments where human dopamine neurons, derived from human ES and patient-derived iPS cells, are transplanted to the striatum in rats with Lewy-like pathology induced by combined α-synuclein/fibril treatment, and study the extent to which α-synuclein pathology will transfer from the affected dopamine neurons to the grafted cells and its effect on transplant survival, growth and function.