Aguzzi Group

The Aguzzi group has successfully established high-throughput screening platforms to assess potential effects of small RNAi on the PrPC biosynthesis, PrPSc pathogenesis and on potential mediators of αSyn aggregation. miRNA screens for PrPC (Pease et al. 2018) and aSyn aggregates as well as a genome wide siRNA screen for effectors of PrPC are completed or almost completed, whereas genome –wide siRNA screens for PrPSc and αSyn aggregates as well as the CRISPR/Cas9-based screen are still ongoing, but are expected to be finished within the next months. Hits from the completed screens – as will be the hits from the ongoing screens- are currently confirmed by either secondary confirmatory screens, differentiating true hits from off-target effects, in other cell lines and by additional orthogonal methods, including RNAseq, CRISPR-Cas9 mediated gene ablation or TRIM-Away (Clift et al, Cell 2017).

After hits confirmation, a data integration and network analysis to identify pathways exploited for genes involved in PrPC biosynthesis and expression, prion pathology or αSyn aggregation, respectively, will be performed. Hits will also further investigated in several disease related model systems.

Overall, we expect that the data obtained from these screens will significantly improve our basic understanding of the mechanisms and pathology in prion diseases and α-synucleinopthies, respectively, and eventually lead to the identification of new therapeutic targets.

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