Washington University School of Medicine

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Marc Diamond, MD

My laboratory is focused on basic research to identify therapeutic targets and develop small molecules to treat human disease. We are especially interested in targeting abnormal protein conformational change, which plays a key role in neurodegenerative diseases such as Huntington disease (HD) and tauopathies. We use a range of approaches: biochemistry, cell and molecular biology, and animal models.

Our work on Huntington disease (HD) focuses on an understanding of protein interactions within the cell that govern the stability of the pathologic protein, huntingtin (Htt). We have created high-throughput approaches to identify chemical and genetic inhibitors of Htt aggregation, and have defined a signaling pathway to the Htt binding protein profilin that is an important therapeutic target. We are developing novel mouse models of HD pathology that exploit the retina as a readout of CNS function, and are using these models to speed analysis of chemical and genetic modifiers in vivo.

The tauopathies constitute a large family of neurodegenerative diseases that include dementias such as Alzheimer disease and motor neuron diseases. All of these diseases feature deposition of aggregated tau protein, and exhibit inexorable spread of pathology. Our work on tau suggests that the aggregates are not static within the cell. Rather, aggregates are taken up by vulnerable cells where they can trigger fibrillization of endogenous, natively folded protein. The newly formed aggregates are capable of moving to neighboring cells to spread pathology. We are determining the molecular basis of these processes, and what is their role in vivo. These prion-like mechanisms of pathology represent a potentially new paradigm in our understanding of neurodegenerative diseases, and could enable a host of new therapeutic strategies based on blocking propagation of misfolding.

Medical Training

Dr. Diamond graduated from Princeton University in 1987 with a BA in History. He entered the UCSF School of Medicine in 1987 and subsequently completed two years of research with Keith Yamamoto, Ph.D. as a Howard Hughes Medical Student Research Fellow. He graduated from UCSF in 1993. Dr. Diamond completed an internship and residency in Neurology at UCSF in 1997, and was then a postdoctoral fellow in the laboratory of Dr. Yamamoto until 2001. He was an assistant, then associate professor in the Neurology Department at UCSF from 2002-2009, before joining the Neurology Department at Washington University in 2009. He is a member of the Hope Center for Neurological Disorders.

Selected Publications

Welch, WJ and Marc I. Diamond: "Glucocorticoid modulation of androgen receptor nuclear aggregation and cellular toxicity is associated with distinct forms of soluble expanded polyglutamine protein"
Human Molecular Genetics, 2001; 10(26):3063-3074

Pollitt, SK, Pallos, J, Shao, J, Desai, UA, Ma, AK, Thompson, LM, Marsh, JL, and Marc I. Diamond: "A rapid cellular FRET assay of polyglutamine aggregation adentifies a novel inhibitor"
Neuron, 2003; 40:685-94

Schaufele, F; Carbonell, X; Guerbadot, M; Borngraeber, S; Ma, AK; Chapman, MS; Miner, JN; and Marc I. Diamond: "The Structural basis of AR activation: intramolecular and intermolecular amino-carboxy interactions"
Proceedings of the National Academy of Sciences, 2005; 102(28):9802-7

Desai UA, Pallos J, Ma AA, Stockwell BR, Thompson LM, Marsh JL and Marc I. Diamond: Biologically active molecules that reduce polyglutamine aggregation and toxicity.
Human Molecular Genetics 2006 Jul 1;15(13):2114-24

Li M, Chevalier-Larsen ES, Merry DE, and Marc I. Diamond: "Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy."
Journal of Biological Chemistry 2007 Feb 2;282(5):3157-64.

Shao, J; Welch, WJ and Marc I. Diamond: "ROCK and PRK-2 mediate the inhibitory effect of Y-27632 on polyglutamine aggregation."
FEBS Letters 2008 582(12):1637-42.

Jones, JO and Marc I. Diamond: " A cellular conformation-based screen for androgen receptor inhibitors"
ACS/Chemical Biology 2008 3(7):412-418

Shao, J; Welch, WJ and Marc I. Diamond: "Phosphorylation of profilin by p160ROCK reduces polyglutamine aggregation"
Molecular and Cellular Biology 2008 28(17):5196-208

Chandra, S; Shao, J; Li, JX; Li, M; Longo, FM, and Marc I. Diamond: "A common motif targets huntingtin and the androgen receptor to the proteasome."
Journal of Biological Chemistry 2008 283(35):23950-5

Frost, B; Ollesch, J; Wille H and Marc I. Diamond: "Conformational diversity of wild-type tau fibrils specified by templated conformational change."
Journal of Biological Chemistry 2009 284(6):3546-51.

Gerber, AN; Misuno, K; and Marc I. Diamond: "Discovery of selective glucocorticoid receptor modulators by multiplexed reporter screening."
Proceedings of the National Academy of Sciences 106(12):4929-34 2009

Jones, JO; Bolton, EC; Huang, Y; Clementine, F; Guy, RK; Yamamoto, KR; Hann, B and Marc I. Diamond: "Ligand independent androgen receptor inhibition in vitro and in vivo."
Proceedings of the National Academy of Sciences 2009 106(17):7233-8

Jones, JO; An, WF, and Marc I. Diamond: "AR Inhibitors identified by high throughput microscopy detection of conformational change and subcellular localization."
ACS/Chemical Biology 2009 4(3):191-7

Frost, B; Jacks, RL; and Marc I. Diamond: "Propagation of tau misfolding from the outside to the inside of a cell."
Journal of Biological Chemistry 2009 284(19):12845-52

Li, M; Huang, Y; Ma, AK; Lin, E; and Marc I. Diamond: "Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice"
Neurobiology of Disease 2009 (in press)