Yeast synuclein models

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Tiago Outeiro and Susan Lindquist (Whitehead Institute, MIT) in 2003; Stacey Willingham, Outeiro, Michael DeVit, Lindquist and Paul Muchowski (University of Washington) in the same year; Antony Cooper, Aaron Gitler, Lindquist and 16 co-authors in 2006. Funders were not checked.

What happened

Alpha-synuclein (landmark 4, landmark 5) misfolds in Parkinson's, but its normal job is unclear.

• Outeiro & Lindquist, Science 2003: in yeast, synuclein stuck to the cell membrane, then formed inclusions through a concentration-dependent process. It inhibited phospholipase D, caused lipid droplets to build up and disturbed vesicle trafficking.
• Willingham et al., Science 2003: a screen of 4,850 yeast gene deletions found 86 that made synuclein more toxic (and 52 for a Huntington's disease protein fragment; only one overlapped). The synuclein hits clustered in lipid metabolism and vesicle transport.
• Cooper et al., Science 2006: the earliest defect was a block in vesicle traffic from the endoplasmic reticulum to the Golgi. The largest group of toxicity modifiers acted at that step. Raising Rab1 (the mammalian version of yeast Ypt1p) protected against synuclein-induced dopamine neuron loss in animal models.

Why it moved us toward a cure

Yeast is cheap and can be screened genome-wide, so it let the field search for synuclein's targets without a hypothesis. It yielded early evidence that synuclein damages basic cell logistics, an idea that sits alongside the lysosome and trafficking branches of the map.

Outcome

Advanced. The same lab later screened for compounds that rescue synuclein toxicity in yeast and found a molecule (an N-aryl benzimidazole) that also protected neurons and worked through the Rsp5/Nedd4 trafficking pathway (Tardiff et al., Science 2013). A yeast cell lacks a dopamine neuron's biology, so hits need testing in neurons. No approved Parkinson's drug came from it.

Sources

• Outeiro & Lindquist, Science 2003;302:1772–1775, DOI 10.1126/science.1090439
• Willingham et al., Science 2003;302:1769–1772, DOI 10.1126/science.1090389
• Cooper et al., Science 2006;313:324–328, DOI 10.1126/science.1129462
• Tardiff et al., Science 2013;342:979–983, DOI 10.1126/science.1245321, PMID 24158909
• Not yet verified: full texts (abstracts only); which animal models Cooper et al. used for the Rab1 rescue (the abstract says "animal models"); whether a yeast-derived compound has entered clinical trials; funders.