Using a lysosomal disorder NPC as a model, the goal of this project is to investigate a role of lysosomal impairment on accumulation of amyloid-beta peptide (Abeta) and alpha-synuclein (a-syn), the two characteristic features in the pathogenesis of AD and PD.We will employ pharmacological treatments and genetic approaches to analyze whether enhancement or inhibition of the lysosomal function can rescue accumulation of Abeta/a-syn and whether their lysosomal clearance may attenuate neurotoxicity and neuronal degeneration.
In addition, we will use state-of-the-art induced pluripotent stem cell technology to generate human NPC neurons by reprogramming the NPC patients’ fibroblasts. The human NPC neurons will be used to validate the relevant targets that are involved in lysosomal function, accumulation of Abeta/a-syn and neurodegeneration. This project will generate new ideas for an effective and highly specific therapy against neurodegenerative diseases, including AD and PD. Our results may provide evidence that lysosomal dysfunction is a common mechanism that leads to neurodegeneration and may lead to development of a novel therapeutic strategy against neurodegenerative disorders.