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DESCRIPTION:\nSupported by the generosity of the Killam Trusts\, The Neuro'
 s Killam Seminar Series invites outstanding guest speakers whose research 
 is of interest to the scientific community at The Neuro and 91ÉçÇø Univers
 ity.\n\n\nRegister Now\n\nTo watch online\, click here\n\n\nDissection of 
 the Prion Life Cycle with Arrayed Genome-Wide CRISPR Screens\n\nAbstract: 
 The Aguzzi lab uses large-scale genetic perturbations to identify factors 
 modifying discrete steps of the prion life cycle. Because most phenotypes 
 relevant to prion biology require complex biochemical assays and are not s
 electable with surface markers\, we resort to arrayed genetic screens in w
 hich the activation or ablation of each gene is tested individually. To ac
 hieve this\, we invented massively parallel plasmid-cloning methodologies 
 to construct arrayed libraries for the genome-wide ablation\, activation a
 nd epigenetic silencing of human genes (42’378 discrete lentiviral vectors
 ). In an arrayed genome-wide CRISPR activation screen\, we identified 80 a
 nd 451 up- and downregulators of PrPC expression\, respectively. 45 of the
  50 strongest modifiers were confirmed in secondary assays. Many of these 
 genes regulated PRNP transcription despite not being canonical transcripti
 on factors\, and some affected PRNP transcription antithetically to PrPC p
 rotein expression\, suggesting posttranscriptional regulation. Other PrPC 
 modifiers impinged on lysosomal degradation\, cholesterol metabolism\, and
  mitochondrial function. Surprisingly\, the strongest PrPC upregulators af
 fected extracellular matrix (ECM) organization. PrPC levels correlated wit
 h ECM abundance\, potentially mediated through mechanosensation of gliotic
  tissue stiffening in prion diseases. Prion entry into cells is a fundamen
 tal step of the prion life cycle\, and its modulation may impact the estab
 lishment and spread of prion infections. A genome-wide CRISPR activation s
 creen for modifiers of prion internalization yielded both expected modulat
 ors and novel candidates. Surprisingly\, the Bone Morphogenetic Protein (B
 MP) pathway stood out as the most enriched pathway. Most members of the BM
 P signal-transduction chain (ligands\, receptors\, transcription factors) 
 lit up in our screens\, with activators and inhibitors leading to increase
 d and decreased prion uptake\, respectively. With a synthetic-lethality sc
 reen we discovered that ciliogenesis is a crucial contributor to Prion tox
 icity. We also identified Heterogenous Nuclear Ribonucleoprotein K (hnRNPK
 ) as a factor limiting prion replication. Little is known about its functi
 on other that it is essential to cell survival. Using a synthetic-viabilit
 y CRISPR ablation screen\, we found that deletion and overexpression of Tr
 anscription Factor AP-2γ (TFAP2C) mitigated and enhanced the death of hnRN
 PK-ablated cells\, respectively. hnRNPK ablation suppressed genes related 
 to lipid and glucose metabolism and enhanced catabolism by modulating mTOR
  and AMPK\, whereas TFAP2C overexpression promoted anabolism. TFAP2C overe
 xpression reduced prion propagation in wild-type cells and neutralized pri
 on accumulation in hnRNPK -suppressed cells. Hence\, TFAP2C and hnRNPK are
  genetic interactors controlling cell metabolism\, bioenergy and prion pro
 pagation. We are now expanding our approach to more prion-related phenomen
 a\, including synuclein phosphorylation after exposure to synthetic prefor
 med synuclein fibrils. Our results showcase the awesome power of unbiased 
 genetic perturbations for the study of neurodegenerative diseases and may 
 enable the identification of novel therapeutically actionable targets.\n\n
 Adriano Aguzzi\n\nProfessor\, Institute of Neuropathology\, University of 
 Zurich\n\nAdriano Aguzzi is professor and director of the Institute of Neu
 ropathology at the University of Zurich. He has devoted the past 25 years 
 to studying the immunological and molecular basis of prion pathogenesis\, 
 combining transgenetics with molecular and immunological techniques to cla
 rify the pathogenesis of the disease\, and to identify cells and molecules
  involved in prion neuroinvasion. He is the Founder and Director of the Sw
 iss National Reference Center for Prion Diseases and has developed diagnos
 tic and therapeutic methods in the field of transmissible spongiform encep
 halopathies. He serves on the editorial board of Science and is the Editor
  in Chief of the Swiss Medical Weekly\; he also serves on the scientific a
 dvisory board of philanthropic foundations and biomedical companies. Among
  other honors\, Prof. Aguzzi has won Ernst-Jung Prize\, the Robert Koch Pr
 ize\, the medal of the European Molecular Biology Organization\, the NOMIS
  Distinguished Scientist Award and has held two ERC Advanced Grants.\n
DTSTART:20250305T180000Z
DTEND:20250305T180000Z
LOCATION:de Grandpre Communications Centre\, The Neuro
SUMMARY:Killam Seminar Series: Dissection of the Prion Life Cycle with Arra
 yed Genome-Wide CRISPR Screens
URL:/neuro/channels/event/killam-seminar-series-dissec
 tion-prion-life-cycle-arrayed-genome-wide-crispr-screens-363887
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