Martin L. Duennwald, Ph.D

Protein misfolding, neurodegenerative diseases, polyglutamine, Huntington’s disease, yeast models

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
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.

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.

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.

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.  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.  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.