Download - Simon Alberti
Aberrant Phase Transitions:
The Cause of Many
Neurodegenerative Disorders?
Simon Alberti
Prions are infectious proteins
Little
structure
Highly ordered,
infectious
prion structure
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.
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.
Prion-like proteins reside in RNP granules
Stress granules
P bodies
Prion-like proteins cause disease
~ 100 prion-like
proteins
FUS
TAF15
EWSR1
hnRPDL
hnRNPD
hnRNPA2B1
hnRNPA1
hnRNPAB
hnRNPA3
TDP-43
TIA-1Disease-causing prion-
like proteins
Fused in sarcoma (FUS)
Healthy control ALS patient
Tony Hyman
FUS forms various compartments
Patel et al., Cell, 2015.
FUS-GFP
FUS forms liquid compartments in vivo
> FUS forms membrane-less liquid-like
compartments in vivo!
FUS-GFP
Patel et al., Cell, 2015.
Reconstituted FUS compartments are liquid-like
> FUS forms liquid compartments in vitro!
FUS-GFP
Patel et al., Cell, 2015.
Prion domain is essential for liquid behavior
PLD
PLD
Patel et al., Cell, 2015.
Prion-like proteins form liquid compartments
PLD
RNP granules
RNA or PAR
Patel et al., Cell, 2015.
What happens in disease?
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
Mutant droplets convert into aggregates
Patel et al., Cell, 2015.
0 hW
TG
15
6E
4 h 8 h
Aberrant phase transitions as a cause of disease
Sup35-GFP
Liquid
Solid
Disease
Aberrant
phase
transition
Patel et al., Cell, 2015.