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Research Article

Accumulation of an Antidepressant in Vesiculogenic Membranes of Yeast Cells Triggers Autophagy

  • Jingqiu Chen equal contributor,

    equal contributor Contributed equally to this work with: Jingqiu Chen, Daniel Korostyshevsky

    Affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America

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  • Daniel Korostyshevsky equal contributor,

    equal contributor Contributed equally to this work with: Jingqiu Chen, Daniel Korostyshevsky

    Affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America

    X
  • Sean Lee,

    Affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America

    X
  • Ethan O. Perlstein mail

    eperlste@princeton.edu

    Affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America

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  • Published: April 18, 2012
  • DOI: 10.1371/journal.pone.0034024

Reader Comments (16)

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Please explain the relevance to humans and concern that ADs cause damage to brain cells.

Posted by sdaviss on 07 May 2012 at 04:03 GMT

Thank you. This is also being discussed on Twitter (#apaam12).

No competing interests declared.

RE: Please explain the relevance to humans and concern that ADs cause damage to brain cells.

eperlste replied to sdaviss on 07 May 2012 at 19:39 GMT

Thanks for your question.

As a general rule, I urge caution when extrapolating from yeast cell physiology to human neuropharmacology. That said, there are several rigorous approaches to translating research from the yeast realm to human biology. I would highly recommend the work of Susan Lindquist's lab as a great real-world example (http://en.wikipedia.org/w...). The Lindquist lab deftly moves between simple non-human model organisms, including yeast, as a way to dissect the root causes of neurodegenerative diseases like Alzheimer's and Parkinson's.

To answer your specific question about the medical relevance of sertraline/Zoloft's cytoxicity, I will respond with two bullet points followed by a slightly more involved explanation:

1) The PLoS ONE paper is not the first to show that antidepressants and other psychiatric-disease drugs are cytotoxic to yeast and different types of mammalian cells. For more on this literature, explore the Wikipedia page for phospholipidosis: http://en.wikipedia.org/w....

2) Dose matters but so does kinetics, i.e., the duration of drug treatment. And without proper context, dose alone is difficult to interpret. For example, genetic studies using the nematode worm C. elegans have been performed at relatively high doses -- up to the double-digit micromolar (µM) range -- but that's largely a function of the worm cuticle, which is the outermost barrier layer of worms. And despite the seemingly high dose, the behavioral effects of the SSRI fluoxetine/Prozac in worms requires serotonin (http://www.jneurosci.org/...).

In contrast to our multicellular and multi-species selves, the yeast Saccharomyces cerevisiae is a special kind of guinea pig: a single cell is the entire organism. That is both a blessing and a curse. From an experimental genetics standpoint, mutant yeast cells that have altered cellular drug responses are really easy to isolate from laboratory cultures, which my lab demonstrated for sertraline/Zoloft in a 2010 paper in the journal Genetics: http://www.genetics.org/c....

The curse is concentration. I acknowledge that sertraline overdose of yeast cells at doses greater than 25µM is considered by some colleagues to be a high concentration. The point of using a high dose is that it enables genetic selection for overdose resistant mutants (please see above blessing). In terms of membrane effects, a micromolar dose of sertraline on a yeast cell population numbering tens of millions of cells ensures rapid onset of membrane changes. However, we showed in the 2010 Genetics paper that sub-lethal doses of sertraline enhances the growth of a specific class of sertraline-overdose-resistant mutants. So the activity of sertraline in yeast is concentration-dependent, specifically "biphasic:" a genetically specific growth-enhancing effect at "low" concentrations and general overdose effect at "high" concentrations. We are now experimentally investigating membrane changes during acute vs chronic treatment in yeast cells and in rat neuronal cell lines in order to understand physiological changes that only occur after chronic, low-dose antidepressant exposure.

No competing interests declared.