Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models.
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.
Su
Linhui Julie
LJ
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Auluck
Pavan K
PK
Outeiro
Tiago Fleming
TF
Yeger-Lotem
Esti
E
Kritzer
Joshua A
JA
Tardiff
Daniel F
DF
Strathearn
Katherine E
KE
Liu
Fang
F
Cao
Songsong
S
Hamamichi
Shusei
S
Hill
Kathryn J
KJ
Caldwell
Kim A
KA
Bell
George W
GW
Fraenkel
Ernest
E
Cooper
Antony A
AA
Caldwell
Guy A
GA
McCaffery
J Michael
JM
Rochet
Jean-Christophe
JC
Lindquist
Susan
S
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
D000978:Antiparkinson Agents; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D012402:Rotenone; D004298:Dopamine