diamond_marc

Marc Diamond, MD

David Clayson Professor of Neurology

Therapeutic Mechanisms in Human Disease: Polyglutamine Disease Pathogensis and Protein Misfolding in Tauopathy Read More

Email: diamondm@neuro.wustl.edu
Lab Phone: (314) 286-2165
Website: Diamond Lab
Lab Location: Biotech 111
Keywords: tauopathy, protein aggregation, neurodegenerative disease, therapy development, molecular mechanisms, prion mechanisms, biophysics, biochemistry, cell and molecular biology, animal models, primary neuronal culture

Therapeutic Mechanisms in Human Disease: Polyglutamine Disease Pathogensis and Protein Misfolding in Tauopathy

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.

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