Rohit Pappu, PhD

Rohit Pappu, PhD

Gene K. Beare Distinguished Professor, WashU Biomedical Engineering

Mechanisms of aggregation and neurodegeneration in polyglutamine expansion disorders, specifically Huntington’s disease

Scientific questions / disorder addressed in the lab

We study intrinsically disordered proteins (IDPs), a class of proteins that perform their biologically relevant functions through heterogeneous ensembles of structures. We are interested in three specific topics pertaining to IDPs namely, their regulated assembly and aberrant self-assembly, mechanisms of molecular recognition particularly DNA and RNA recognition by IDPs, and the design of novel IDPs that will be of use in manipulating transcriptional networks. In the area of aberrant self-assembly we are studying the mechanisms of aggregation of polyglutamine containing proteins, primarily of the protein huntingtin that is involved in the onset and progression of Huntington’s disease. We are also studying the interplay between aggregation and functional in vivo interactions in order to understand how aggregation contributes to specificity in neurodegeneration. In addition, we are identifying common themes in the mechanisms of aggregation through comparative studies of proteins involved in eight other neurodegenerative disorders that are associated with polyglutamine expansions such as spinocerebellar ataxias as well the proteins Tau and amyloid beta whose aggregation is associated with Alzheimer’s disease. Our focus at this juncture is on the interplay between cis and trans modulation of protein aggregation i.e., the interplay between the sequence contexts of aggregation prone regions and the effects of endogenous intracellular proteins and professional extracellular chaperones on protein aggregation. We expect to mimic or enhance the effects of cis and trans modulators to regulate aggregation and affect cell fate.

Techniques or approaches used in the lab

Our main tools are biophysical in nature. Although we are recognized mainly for our strengths in computer simulations and adaptations of polymer physics theories, we have recently expanded our toolkit to include a range of in vitro methods that incorporate the entire spectrum of established and cutting edge fluorescence spectroscopies and morphological studies aided by atomic force and electron microscopy.  Some of this infrastructure has been set up within the molecular spectroscopy core of the Center for Biological Systems Engineering. We also work closely with Hope Center investigators who enable us to translate our ideas into cellular and animal model settings.

More about the Pappu lab