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Articles by S. Lindquist
Total Records ( 2 ) for S. Lindquist
  L. J Su , P. K Auluck , T. F Outeiro , E Yeger Lotem , J. A Kritzer , D. F Tardiff , K. E Strathearn , F Liu , S Cao , S Hamamichi , K. J Hill , K. A Caldwell , G. W Bell , E Fraenkel , A. A Cooper , G. A Caldwell , J. M McCaffery , J. C Rochet and S. Lindquist
  Linhui Julie Su, Pavan K. Auluck, Tiago Fleming Outeiro, Esti Yeger-Lotem, Joshua A. Kritzer, Daniel F. Tardiff, Katherine E. Strathearn, Fang Liu, Songsong Cao, Shusei Hamamichi, Kathryn J. Hill, Kim A. Caldwell, George W. Bell, Ernest Fraenkel, Antony A. Cooper, Guy A. Caldwell, J. Michael McCaffery, Jean-Christophe Rochet, and Susan Lindquist

-Synuclein (-syn) is a small lipid-binding protein involved in vesicle trafficking whose function is poorly characterized. It is of great interest to human biology and medicine because -syn dysfunction is associated with several neurodegenerative disorders, including Parkinson’s disease (PD). We previously created a yeast model of -syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to -syn expression. We also uncovered a core group of proteins with diverse activities related to -syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of -syn also exhibits strong defects in mitochondrial function. Unlike our previous strain, genetic suppression of endoplasmic reticulum (ER)-to-Golgi trafficking alone does not suppress -syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of -syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced -syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of -syn foci, re-established ER-to-Golgi trafficking and ameliorated -syn-mediated damage to mitochondria. They also corrected the toxicity of -syn in nematode neurons and in primary rat neuronal midbrain cultures. Remarkably, the compounds also protected neurons against rotenone-induced toxicity, which has been used to model the mitochondrial defects associated with PD in humans. That single compounds are capable of rescuing the diverse toxicities of -syn in yeast and neurons suggests that they are acting on deeply rooted biological processes that connect these toxicities and have been conserved for a billion years of eukaryotic evolution. Thus, it seems possible to develop novel therapeutic strategies to simultaneously target the multiple pathological features of PD.

  J. C.S Brown and S. Lindquist
 

Several well-characterized fungal proteins act as prions, proteins capable of multiple conformations, each with different activities, at least one of which is self-propagating. Through such self-propagating changes in function, yeast prions act as protein-based elements of phenotypic inheritance. We report a prion that makes cells resistant to the glucose-associated repression of alternative carbon sources, [GAR+] (for "resistant to glucose-associated repression," with capital letters indicating dominance and brackets indicating its non-Mendelian character). [GAR+] appears spontaneously at a high rate and is transmissible by non-Mendelian, cytoplasmic inheritance. Several lines of evidence suggest that the prion state involves a complex between a small fraction of the cellular complement of Pma1, the major plasma membrane proton pump, and Std1, a much lower-abundance protein that participates in glucose signaling. The Pma1 proteins from closely related Saccharomyces species are also associated with the appearance of [GAR+]. This allowed us to confirm the relationship between Pma1, Std1, and [GAR+] by establishing that these proteins can create a transmission barrier for prion propagation and induction in Saccharomyces cerevisiae. The fact that yeast cells employ a prion-based mechanism for heritably switching between distinct carbon source utilization strategies, and employ the plasma membrane proton pump to do so, expands the biological framework in which self-propagating protein-based elements of inheritance operate.

 
 
 
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