Simon Alberti
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The document discusses the connection between aberrant phase transitions of prion-like proteins and neurodegenerative disorders. It highlights features of these proteins, their behavior in cellular compartments, and how mutations can lead to aggregation and disease. Key examples include FUS and TDP-43, which are implicated in conditions like ALS.
Simon Alberti
- 1. Aberrant Phase Transitions: The Cause of Many Neurodegenerative Disorders? Simon Alberti
- 2. Prions are infectious proteins Little structure Highly ordered, infectious prion structure
- 3. Sequence features of budding yeast prions - Mostly polar and aromatic amino acids - Low sequence complexity - Contains information for prion behavior - Intrinsically disordered > Algorithm to predict prion-like proteins Alberti et al., Cell, 2009.
- 4. Predicting prion-like proteins in humans ~ 100 prion-like proteins FUS TAF15 EWSR1 hnRPDL hnRNPD hnRNPA2B1 hnRNPA1 hnRNPAB hnRNPA3 TDP-43 TIA-1 King et al., Brain Res., 2012; Malinovska et al., BBA, 2013.
- 5. Prion-like proteins reside in RNP granules Stress granules P bodies
- 6. Prion-like proteins cause disease ~ 100 prion-like proteins FUS TAF15 EWSR1 hnRPDL hnRNPD hnRNPA2B1 hnRNPA1 hnRNPAB hnRNPA3 TDP-43 TIA-1 Disease-causing prion- like proteins
- 7. Fused in sarcoma (FUS) Healthy control ALS patient Tony Hyman
- 8. FUS forms various compartments Patel et al., Cell, 2015. FUS-GFP
- 9. FUS forms liquid compartments in vivo > FUS forms membrane-less liquid-like compartments in vivo! FUS-GFP Patel et al., Cell, 2015.
- 10. Reconstituted FUS compartments are liquid-like > FUS forms liquid compartments in vitro! FUS-GFP Patel et al., Cell, 2015.
- 11. Prion domain is essential for liquid behavior PLD PLD Patel et al., Cell, 2015.
- 12. Prion-like proteins form liquid compartments PLD RNP granules RNA or PAR Patel et al., Cell, 2015.
- 13. What happens in disease?
- 14. FUS droplets change their physical properties WT FUS Mutant FUS (G156E) Patel et al., Cell, 2015. 0 s 90 s 185 s 0 s 3.6 s 5 s Fusion No fusion
- 15. Mutant droplets convert into aggregates Patel et al., Cell, 2015. 0 h WTG156E 4 h 8 h
- 16. Aberrant phase transitions as a cause of disease Sup35-GFP Liquid Solid Disease Aberrant phase transition Patel et al., Cell, 2015.