NFL Long Study | Kun Ping Lu

Dr. Lu is a Professor at Harvard Medical School, the Chief of Division of Translational Therapeutics at Beth Israel Deaconess Medical Center and an Associate Member of Broad Institute of MIT and Harvard. He has pioneered in elucidating the role of protein conformational regulation after proline-directed phosphorylation in health and disease. In working with the long-term collaborator Dr. Xiao Zhen Zhou, Dr. Lu has identified an unique enzyme called Pin1 that catalyzes proline cis-trans isomerization after phosphorylation, leading the discovery of post-phosphorylation conformational regulation as a new signaling mechanism. His lab is the first one to show that Pin1 is highly regulated physiologically, and its deregulation has the pivotal but opposite effects on the development of cancer and Alzheimer’s disease. These are two major age-related diseases that were rarely studied together before, but are now accepted to be two sides of the same coin. Importantly, their new insights into the disease mechanisms have led to promising new diagnostics and therapeutics targeting Pin1-catalyzed protein conformational changes. Notably, in Alzheimer’s, Pin1 helps protect against neurodegeneration by converting phosphorylated tau from the pathogenic cis conformation to the physiologic trans. To detect Pin1-catalyzed conformational changes, Dr. Zhou and Dr. Lu develops innovative technology to generate antibodies able to distinguish these two different conformations. These unique antibodies have led to the surprising discovery that pathogenic cis tau is a precursor of tau pathology that provides the first causal molecular link between traumatic brain injury and chronic traumatic encephalopathy, but is effectively targeted by immunotherapy to stop neurodegeneration after TBI. Their current focuses are to establish cis tau as a biomarker for identifying and stratifying outcomes of brain injury/chronic traumatic encephalopathy, and Alzheimer’s patients, to humanize their murine cis tau antibody suitable for use in clinical trials, and to understand why certain people are more resistant to brain injury.