Aged-induced Organoids for studying Parkinson’s Disease

Parkinsons disease (PD) is the second most common neurodegenerative disorder, affecting about 10 million people worldwide. People with PD suffer from a degeneration of neurons that produce the neurotransmitter dopamine, which is particularly crucial for normal movement. There is currently no cure for this disease, but only treatments to reduce the symptoms. The pathological hallmarks of PD are intracellular inclusions of proteins called Lewy bodies that are predominantly formed of aggregated forms of a protein called alpha-Synuclein. While the exact cause of PD is unknown, a small percentage (5 to 10%) of patients has been identified with single mutations obviously causing the disease, but the majority of cases are sporadic without genetic cause. A number of studies have highlighted that advanced age and neuroinflammation are important risk factors for PD onset. However, further advances in improving our understanding about the mechanisms of neuron degeneration and PD etiology is still unclear. This is mainly due to the fact that it is very difficult to study the disease in the human brain and animal models do not fully recapitulate the human physiology. Therefore, a human model that can recapitulate more disease features is highly needed. In this study, we hypothesise that human in vitro models using induced pluripotent stem cells (iPSC), taken from PD patients with genetic and sporadic background, can be used to investigate the relation between the PD main risk factors: aging, neuroinflammation and alpha-Synuclein. For this purpose, we will generate 3 different region-specific in vitro models of human mini brains, designated as organoids. Organoids are three dimensional cellissue culture outcomes, which leverages the ability of cells to self-assemble or/and self-organize into tissues, aiming to generate a microenvironment that mimics the organ structure and function in the living organism. To better represent the disease progression, we will induce aging in all the models by overexpression a protein called Progerin, that has been shown to accelerate aging in cells. State of the art cellular and molecular biology techniques, cell imaging as well as transcriptomics and proteomics will be performed in the analysis. By assessing the novel PD in vitro models we propose, combined with extensive cellular and molecular analysis, we expect to find novel PD biomarkers that may help to predict the development of the disease at early stages. Moreover, the analysis will enable to reveal key elements that will help in understanding the disease for the outmost goal to develop new medications that prevent or cure PD.