Lysosomes are specific cellular organelles that are normally involved in degradation processes of proteins and other damaged organelles. Dysfunction of lysosomes may lead to abnormal protein accumulation which may cause cell degeneration and death. Such protein accumulation also occurs in the brain cells and triggers development of the devastating neurodegenerative diseases in humans, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).

Although AD and PD are the most common neurodegenerative diseases, there are still no adequate therapies that would prevent or cure AD and PD. In addition, the underlying cellular processes which lead to AD and PD are still not completely understood. In this project we will employ our knowledge and use modern and sophisticated technologies to unravel a molecular mechanism that leads to AD and PD in order to develop targeted and effective future therapies. Recent studies suggest that dysregulation of lysosomes may result in protein accumulation and neurodegeneration. Additionally, it is intriguing that several human rare inherited disorders caused by dysfunction of the lysosomal proteins, such as Niemann-Pick type C disease (NPC), show neurodegeneration and accumulation of proteins characteristic for AD and PD.

Although these findings provide a further evidence for the link between lysosomal dysfunction, protein accumulation and neurodegenerative processes, molecular details of this relationship are largely unknown.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.