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Aberrant Phase Transitions: The Cause of Many Neurodegenerative Disorders? Simon Alberti

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Page 1: Simon Alberti

Aberrant Phase Transitions:

The Cause of Many

Neurodegenerative Disorders?

Simon Alberti

Page 2: Simon Alberti

Prions are infectious proteins

Little

structure

Highly ordered,

infectious

prion structure

Page 3: Simon Alberti

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.

Page 4: Simon Alberti

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.

Page 5: Simon Alberti

Prion-like proteins reside in RNP granules

Stress granules

P bodies

Page 6: Simon Alberti

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

Page 7: Simon Alberti

Fused in sarcoma (FUS)

Healthy control ALS patient

Tony Hyman

Page 8: Simon Alberti

FUS forms various compartments

Patel et al., Cell, 2015.

FUS-GFP

Page 9: Simon Alberti

FUS forms liquid compartments in vivo

> FUS forms membrane-less liquid-like

compartments in vivo!

FUS-GFP

Patel et al., Cell, 2015.

Page 10: Simon Alberti

Reconstituted FUS compartments are liquid-like

> FUS forms liquid compartments in vitro!

FUS-GFP

Patel et al., Cell, 2015.

Page 11: Simon Alberti

Prion domain is essential for liquid behavior

PLD

PLD

Patel et al., Cell, 2015.

Page 12: Simon Alberti

Prion-like proteins form liquid compartments

PLD

RNP granules

RNA or PAR

Patel et al., Cell, 2015.

Page 13: Simon Alberti

What happens in disease?

Page 14: Simon Alberti

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

Page 15: Simon Alberti

Mutant droplets convert into aggregates

Patel et al., Cell, 2015.

0 hW

TG

15

6E

4 h 8 h

Page 16: Simon Alberti

Aberrant phase transitions as a cause of disease

Sup35-GFP

Liquid

Solid

Disease

Aberrant

phase

transition

Patel et al., Cell, 2015.