Martin L. Duennwald, Ph.D.
Scientist
Protein misfolding, neurodegenerative diseases, polyglutamine, Huntington's disease, yeast models
Email: duennwald at bbri.org

Research Summary
Proteins only function properly after folding into their accurate three-dimensional conformation. Consequently, the misfolding of proteins can have catastrophic effects as exemplified by neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (HD). There are no effective therapies for any of these disorders and our understanding of their molecular pathology is limited. Focusing on HD we aim to decipher the basic toxic mechanisms of protein misfolding and devise new effective therapeutic approaches. To this end we exploit experimental models, including yeast, cultured neurons, and mice and a combination of genetic, biochemical, and cell biological experimental approaches.

Selected Publications

Roberts BE, Duennwald ML, Wang H, Chung C, Lopreiato NP, Sweeny EA, Knight MN, Shorter J. A synergistic small-molecule combination directly eradicates diverse prion strain structures. Nat Chem Biol. 2009 Dec;5(12):936-46. Epub 2009 Nov 1. PMID: 19915541

Duennwald ML and Lindquist S. Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity. Genes & Development. 2008;22, 3308-19.

Duennwald ML. Chaperones and polyglutamine expansion disorders. In Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection (Asea, A. A. & Brown, I. R., eds.), 2008; Vol. 3, pp. 3-23. Springer Netherlands.

Douglas PM, Treusch S, Ren HY, Halfmann R, Duennwald ML, Lindquist S, Cyr DM. Chaperone-dependent amyloid assembly protects cells from prion toxicity. Proc Natl Acad Sci U S A. 2008;105(20):7206-11. View Full Text (PDF).

Wang H, Duennwald ML, Roberts BE, Rozeboom LM, Zhang YL, Steele AD, Krishnan R, Su LJ, Griffin D, Mukhopadhyay S, Hennessy EJ, Weigele P, Blanchard BJ, King J, Deniz AA, Buchwald SL, Ingram VM, Lindquist S, Shorter J. Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and analogs. Proc Natl Acad Sci U S A. 2008;105(20):7159-64. View Full Text (PDF).

Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, Legleiter J, Marsh JL, Thompson LM, Lindquist S, Muchowski PJ, Wanker EE. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models. Hum Mol Genet. 2006;15(18):2743-51. View Full Text (PDF).

Duennwald ML, Jagadish S, Giorgini F, Muchowski PJ, Lindquist S. A network of protein interactions determines polyglutamine toxicity. Proc Natl Acad Sci U S A. 2006;103(29):11051-6. View Full Text (PDF).

Duennwald ML, Jagadish S, Muchowski PJ, Lindquist S. Flanking sequences profoundly alter polyglutamine toxicity in yeast. Proc Natl Acad Sci U S A. 2006;103(29):11045-50. View Full Text (PDF). 

Cashikar AG, Duennwald M, Lindquist SL. A chaperone pathway in protein disaggregation. Hsp26 alters the nature of protein aggregates to facilitate reactivation by Hsp104. J Biol Chem. 2005;280(25):23869-75. View Full Text (PDF), ERRATUM, J Biol Chem. 2006;281(13):8996.

Colby DW, Chu Y, Cassady JP, Duennwald M, Zazulak H, Webster JM, Messer A, Lindquist S, Ingram VM, Wittrup KD. Potent inhibition of huntingtin aggregation and cytotoxicity by a disulfide bond-free single-domain intracellular antibody. Proc Natl Acad Sci U S A. 2004;101(51):17616-21. View Full Text (PDF), ERRATUM, Proc Natl Acad Sci U S A. 2005;102(3):955.

Dünnwald M, Varshavsky A, Johnsson N. Detection of transient in vivo interactions between substrate and transporter during protein translocation into the endoplasmic reticulum. Mol Biol Cell. 1999;10(2):329-44. View Full Text (PDF).

PubMed:PubMed:
Click here for a list of publications (searches the National Library of Medicine's PubMed database.)