title: Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models.
abstract: alpha-Synuclein (alpha-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 alpha-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson's disease (PD). We previously created a yeast model of alpha-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to alpha-syn expression. We also uncovered a core group of proteins with diverse activities related to alpha-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of alpha-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 alpha-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of alpha-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced alpha-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of alpha-syn foci, re-established ER-to-Golgi trafficking and ameliorated alpha-syn-mediated damage to mitochondria. They also corrected the toxicity of alpha-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 alpha-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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Linhui Julie
authors.initials: LJ
authors.lastname: Su
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Auluck
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
authors.forename: Esti
authors.initials: E
authors.lastname: Yeger-Lotem
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Kritzer
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Tardiff
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Strathearn
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Songsong
authors.initials: S
authors.lastname: Cao
authors.forename: Shusei
authors.initials: S
authors.lastname: Hamamichi
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Hill
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: George W
authors.initials: GW
authors.lastname: Bell
authors.forename: Ernest
authors.initials: E
authors.lastname: Fraenkel
authors.forename: Antony A
authors.initials: AA
authors.lastname: Cooper
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: J Michael
authors.initials: JM
authors.lastname: McCaffery
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rochet
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D020869:Gene Expression Profiling; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000633:toxicity
chemical_list: D000978:Antiparkinson Agents; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D012402:Rotenone; D004298:Dopamine