Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models

Dis Model Mech. Mar-Apr 2010;3(3-4):194-208. doi: 10.1242/dmm.004267. Epub 2009 Dec 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology
  • Antiparkinson Agents / therapeutic use*
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / metabolism
  • Disease Models, Animal
  • Dopamine / metabolism
  • Drug Evaluation, Preclinical
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • Gene Expression Profiling
  • Golgi Apparatus / drug effects
  • Golgi Apparatus / metabolism*
  • Golgi Apparatus / ultrastructure
  • Mitochondria / drug effects
  • Mitochondria / pathology*
  • Mitochondria / ultrastructure
  • Neurons / drug effects
  • Neurons / pathology
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / metabolism*
  • Protein Transport / drug effects
  • Rats
  • Reactive Oxygen Species / metabolism
  • Rotenone / toxicity
  • Saccharomyces cerevisiae / drug effects
  • Stress, Physiological / drug effects
  • Structure-Activity Relationship
  • alpha-Synuclein / toxicity

Substances

  • Antiparkinson Agents
  • Reactive Oxygen Species
  • alpha-Synuclein
  • Rotenone
  • Dopamine

Associated data

  • GEO/GSE11633