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Research Interests

Keywords: Neurodegenerative diseases, aging, protein misfolding, protein quality control

Description of Research Activities

All proteins must attain their distinct three-dimensional conformation to function properly. Consequently, accurate protein folding is essential for all biological processes in all living organisms, including the human body. Cellular mechanisms of protein quality control, such as chaperoning proteins folding, protein re-folding, and protein degradation, assure correct protein function and prevent protein misfolding. Yet, cellular protein quality control fails in many human diseases, particularly neurodegenerative diseases, causing protein misfolding with its toxic consequences. Environmental factors, genetic mutations, and aging contribute to the failure of protein quality control and thus to protein misfolding.

Research in my lab aims to decipher the cellular mechanisms underpinning the interplay of failing cellular protein quality control and protein misfolding. As a paradigm for protein misfolding diseases, we focus on diseases caused by the abnormal expansion of polyglutamine regions, called protein expansion diseases, such as Huntington’s disease and the Spinocerebellar Ataxias. In a combination of genetic, cell biological, and biochemical approaches we employ the model organism yeast, as well as cultured mammalian cells, neurons, and work with purified proteins, to address basic questions regarding the pathogenesis of protein misfolding diseases. We thus seek to decipher the molecular and cellular mechanisms of protein misfolding diseases and to identify promising new therapeutic approaches for their treatment.

Selected Publications

1. Duennwald ML, Echeverria A, Shorter J. Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans. PLoS Biol. 2012 Jun;10(6):e1001346. Epub 2012 Jun 19. PMID:22723742.
2. Chafekar SM, Wisén S, Thompson AD, Echeverria A, Walter GM, Evans CG, Makley LN, Gestwicki JE, Duennwald ML (2012). Pharmacological Tuning of Heat Shock Protein 70 Modulates Polyglutamine Toxicity and Aggregation. ACS Chem Biol. 2012 Jun 22. PMID:22709427.
3. Sidhartha M. Chafekar and Martin L. Duennwald (2012). Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin. PLoS One;7(5). PMID:22649566.
4. Martin L. Duennwald (2012). Polyglutamine misfolding in yeast: toxic and protective aggregation. Prion, 1;5(4). PMID:22052348.
5. Blake E. Roberts, Martin L. Duennwald*, Huan Wang, Chan Chung, Nick Lopreiato, Elizabeth A. Sweeny, M. Noelle Knight, and James Shorter (2009). Direct and synergistic eradication of diverse prion strain structures using a small molecule combination. Nature Chemical Biology, 5(12):936-46. NIHMS144138. *Co-first and co-corresponding (senior) author.