Different 8-hydroxyquinolines Protect Models of TDP-43 Protein, α-synuclein, and Polyglutamine Proteotoxicity Through Distinct Mechanisms

J Biol Chem. 2012 Feb 3;287(6):4107-20. doi: 10.1074/jbc.M111.308668. Epub 2011 Dec 6.

Abstract

No current therapies target the underlying cellular pathologies of age-related neurodegenerative diseases. Model organisms provide a platform for discovering compounds that protect against the toxic, misfolded proteins that initiate these diseases. One such protein, TDP-43, is implicated in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In yeast, TDP-43 expression is toxic, and genetic modifiers first discovered in yeast have proven to modulate TDP-43 toxicity in both neurons and humans. Here, we describe a phenotypic screen for small molecules that reverse TDP-43 toxicity in yeast. One group of hit compounds was 8-hydroxyquinolines (8-OHQ), a class of clinically relevant bioactive metal chelators related to clioquinol. Surprisingly, in otherwise wild-type yeast cells, different 8-OHQs had selectivity for rescuing the distinct toxicities caused by the expression of TDP-43, α-synuclein, or polyglutamine proteins. In fact, each 8-OHQ synergized with the other, clearly establishing that they function in different ways. Comparative growth and molecular analyses also revealed that 8-OHQs have distinct metal chelation and ionophore activities. The diverse bioactivity of 8-OHQs indicates that altering different aspects of metal homeostasis and/or metalloprotein activity elicits distinct protective mechanisms against several neurotoxic proteins. Indeed, phase II clinical trials of an 8-OHQ has produced encouraging results in modifying Alzheimer disease. Our unbiased identification of 8-OHQs in a yeast TDP-43 toxicity model suggests that tailoring 8-OHQ activity to a particular neurodegenerative disease may be a viable therapeutic strategy.

Publication types

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

MeSH terms

  • Animals
  • Caenorhabditis elegans
  • Chelating Agents / pharmacology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Ionophores / pharmacology
  • Models, Biological*
  • Oxyquinoline / pharmacology*
  • Polyglutamic Acid / genetics
  • Polyglutamic Acid / metabolism*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • TDP-43 Proteinopathies / drug therapy*
  • TDP-43 Proteinopathies / genetics
  • TDP-43 Proteinopathies / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Chelating Agents
  • DNA-Binding Proteins
  • Ionophores
  • alpha-Synuclein
  • Polyglutamic Acid
  • Oxyquinoline