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.