Grant: Project Grant

Parkinson's disease (PD) is a devastating neurodegenerative disorder affecting over 2% of the worldwide population. Classical hallmarks of this disorder are a progressive loss of cells from the brain, and an accumulation of protein clumps termed Lewy bodies (LBs). LBs are observed early in the development of PD, and imaging studies have shown that these LBs can move throughout the brain ultimately leading to a loss of cells within the brains of PD patients. The predominant component of these clumps is alpha-synuclein (alpha-syn), with recent studies identifying a new disease-causing mechanism by which alpha-syn can move from cell to cell, acting as a template to seed new clumps. Thus, preventing the spread of these toxic alpha-syn seeds represents an attractive therapeutic approach. However, to date much is still unknown about how these inclusions form and move around within the brain using animal models. To move away from animal models, and to understand better how alpha-syn acts, we are proposing to use cells present within the human brain to gain insight into the mechanisms behind this devastating human disease. For making these cells from the brain, we will take advantage of new stem cell technology, in which we can form stem cells from a person's skin or blood. These induced stem cells, or iPSCs; can be directed into flat 2D neuronal networks on a dish, or into a free-floating 3D spherical interconnected neuronal structures, termed minibrains. Using these human models, we will perform a comprehensive study to understand what cells are the the main receiving/distribution hubs for making and moving these clumps between cells. By working in two different types of human models, we believe our findings will translate more effectively into our understanding of PD and illuminate how these toxic clumps traverse the brain, accompanied by a progressive loss of cells and a worsening in PD symptoms.