Prion diseases are fatal neurodegenerative diseases and are caused by proteinaceous infectious particles termed prions. The infectious agent of prion diseases has been identified decades ago, but the actual cellular processes that subsequently cause neurons to degenerate remain poorly understood. While the mechanisms leading to neurodegeneration are largely unknown, several molecular pathways have been implicated to play a role. Interestingly, the same pathways as well as protein aggregation, have also been linked to other neurodegenerative diseases including Alzheimer’s Disease and Parkinson’s Disease. While these neurodegenerative diseases have a distinct pathology, they might share a common mechanism of protein misfolding induced neuronal death. This is particularly interesting as the prion mouse model recapitulates the human disease more faithfully than other neurodegenerative disease mouse models. With more than 50 million people suffering from neurodegenerative diseases worldwide, and no treatment options being available that prevent or even just slow down their progression, neurodegenerative diseases represent a major burden for patients, their families as well as our society. By advancing our understanding of neurodegenerative diseases, this project has thus a major impact on our society.
The molecular underpinnings of prion disease pathology are beginning to get unraveled, yet a detailed mechanistic understanding of the deleterious effects of prions is missing. A thorough analysis of the molecular changes during disease progression is therefore key to developing a deeper understanding of how prions escape immune surveillance and eventually lead to neuronal cell death. Curiously, few tissues have been shown to replicate prions, and prions induce cell loss, plaque formation and vacuole accumulation only in the brain. Moreover, some cell types can clear prions under certain conditions, suggesting that the expression of co-factors regulates whether prions are cleared, replicate or exert toxicity. While it is currently unknown why different cell types undergo distinct fates upon prion infection, these observations emphasize the importance of studying prion disease in a cell-type specific manner.
The proposed project entailed the systematic and unbiased analysis of genome-wide cell-type specific molecular changes during prion disease pathogenesis in vivo. The assessment of multiple time points following prion infection allows the dissection of the dynamics of disease manifestation. Furthermore, focusing specifically on cells that are relevant to prion disease, sheds light on the role and interplay of the analyzed cell types. The thereby generated data yields novel and important insights into prion disease pathophysiology, and additionally contributes to our understanding of other neurodegenerative diseases.
