We are an internationally-recognized team studying Alzheimer’s disease, Tauopathies and prion disorders. Our research builds on the hypothesis that the most promising early diagnostics and disease intervention strategies will emerge from an in-depth understanding of disease etiologies. More specifically, the primary objective of our work is to understand (1) how the amyloid precursor protein (APP) gives rise to the Abeta (Aβ) fragment through endoproteolyitc cleavage, (2) how binding of Aβ to the prion protein (PrP) signals to Tau, and (3) how Tau aggregation causes cellular toxicity. Highlights of our work are the discovery of key molecular interactions of the γ-secretase, the amyloid precursor protein (APP), the Aβ peptide, PrP, and the Tau protein. For both PrP and Tau, the quantitative interactome data we generated were the first to become available, for other bait proteins our analyses were more thorough than previously published studies.
Discovery research of this kind can reveal unexpected molecular connections that may escape traditional research approaches. For example, we discovered critical roles of Lingo-1, PrP, and Tmp21 in the proteolytic cleavage of APP. In 2009, we uncovered the evolutionary origins of the prion gene family from the family of ZIP metal ion transporters. Thus, although our work often begins with the discovery of novel protein interactions, most of our time is spent adding value to these lead discoveries by elucidating insights that can make a difference to people in the clinic. In the latter example, knowing about the evolutionary link of PrP to ZIPs was critical for recognizing a role of PrP during cellular reprogramming underlying epithelial-to-mesenchymal transitions. This, in turn, precipitated our most recent discovery of a signaling loop that emanates from PrP and controls NCAM1 polysialylation. This insight is not only a milestone in efforts to reveal PrP’s elusive function but may be critical for understanding how cells die in AD and prion diseases.
Dr. Gerold Schmitt-Ulms trained in the laboratory of Nobel Laureate Dr. Stanley Prusiner at the University of California, San Francisco, before joining the Tanz Centre for Research in Neurodegenerative Diseases (Tanz CRND). He is an Associate Professor and Graduate Faculty Member of the Department of Laboratory Medicine & Pathology (LM&P) and a Member of the Collaborative Program in Neuroscience (CPIN), University of Toronto.