TDP-43 toxicity in yeast

Maria Armakola, Michael P. Hart, Aaron D. Gitler*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

22 Scopus citations

Abstract

The budding yeast Saccharomyces cerevisiae is an emerging tool for investigating the molecular pathways that underpin several human neurodegenerative disorders associated with protein misfolding. Amyotrophic lateral sclerosis (ALS) is a devastating adult onset neurodegenerative disease primarily affecting motor neurons. The protein TDP-43 has recently been demonstrated to play an important role in the disease, however, the mechanisms by which TDP-43 contributes to pathogenesis are unclear. To explore the mechanistic details that result in aberrant accumulation of TDP-43 and to discover potential strategies for therapeutic intervention, we employed a yeast TDP-43 proteinopathy model system. These studies allowed us to determine the regions of TDP-43 required for aggregation and toxicity and to define the effects of ALS-linked mutant forms of TDP-43. We have also been able to harness the power of yeast genetics to identify potent modifiers of TDP-43 toxicity using high-throughput yeast genetic screens. Here, we describe the methods and approaches that we have used in order to gain insight into TDP-43 biology and its role in disease. These approaches are readily adaptable to other neurodegenerative disease proteins.

Original languageEnglish (US)
Pages (from-to)238-245
Number of pages8
JournalMethods
Volume53
Issue number3
DOIs
StatePublished - Mar 1 2011
Externally publishedYes

Keywords

  • ALS
  • Human disease
  • Neurodegeneration
  • Protein misfolding
  • Screens
  • TDP-43
  • Yeast

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)

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