Alzheimer's Disease Research - Current Award
Sangram Sisodia, Ph.D.
University of Chicago
Chicago, IL, United States
Title: Structure and Functional Analysis of Nicastrin
Non-Technical Title: Defining the Structural Basis of Nicastrin Function
Shohei Koide, Ph.D.
University of Chicago
Duration: July 1, 2011 - June 30, 2013
Award Type: Standard
Award Amount: $150,000
Gamma-secretase is a complex of membrane proteins consisting of presenilin 1 or presenilin 2 (PS1 or PS2), APH-1, nicastrin (NCT) and PEN-2. It is now certain that PS serves as the catalytic center of the complex, but our understanding of the roles of the individual components in promoting gamma-secretase activity is still limited. We have chosen to examine NCT, a molecule proposed to serve as a receptor that facilitates engagement of the substrate with the catalytic site. The central aim of our study is to understand the structure and function of NCT with the notion that we will gain insights into the differential recognition of substrates, information that will be of immense interest in academic and pharmaceutical interests that are focused on the development of novel gamma secretase modulators as therapeutics for AD.
Beta‐amyloid, the sticky protein that is the main component of brain plaques in Alzheimer's disease, is created by clipping it from a bigger protein, called beta‐amyloid precursor protein (APP). This clipping of APP is done by gamma secretase, a bundle of proteins that includes presenilin 1 or 2, APH‐1, PEN‐2, and nicastrin (NCT). NCT is the part of the bundle that recognizes and pulls into the complex many of the proteins, including APP, that are then processed by the rest of the gamma secretase proteins. Drs. Sangram Sisodia, Shohei Koide, and collaborators will study the shape of NCT to better understand how it partners with other proteins. They will make antibodies that bind like a lock and key to different parts of NCT to aid in their analysis. Once the shape of NCT is determined, the next step will be to design and test new drugs to specifically block NCT from binding to APP and, as a result, prevent the creation of beta‐amyloid.
Dr. Sisodia’s and Dr. Koide’s team has examined the function of nicastrin (NCT) protein, a part of the gamma secretase complex. NCT is proposed to serve as a receptor that recognizes and pulls in many targets, including the APP protein, that are then processed by the rest of the complex. Over the past year, the team has discovered a novel domain in NCT that they believe is a “substrate recognition motif” (the part of the protein that specifically targets proteins to be pulled into the complex). Since this complex is responsible for creating toxic beta-amyloid after processing the APP protein, this exciting result offers significant support for the future development of novel gamma secretase modulators as therapeutics for AD.
Dr. Sangram Sisodia received his B.A. from the College of Wooster in Ohio and his Ph.D. in Biochemistry from the University of Georgia. He joined the Johns Hopkins University School of Medicine as a Postdoctoral Fellow in 1985, where he rose to the rank of Professor of Pathology and Neuroscience. He then moved to the University of Chicago in 1998 to assume the chairmanship in the Department of Neurobiology, Pharmacology and Physiology. He is currently the Thomas Reynolds Sr. Family Professor of Neuroscience and Director of the Center for Molecular Neurobiology in the Department of Neurobiology at the University of Chicago. His research has focused on understanding the cellular and molecular biology of the amyloid precursor protein (APP) and presenilins (PS1 and PS2) that are mutated in pedigrees with familial Alzheimer's Disease (FAD). He was the first to define the biosynthesis, processing, and trafficking of APP in mammalian cells in vitro and to establish that neuronal APP is rapidly transported and processed at terminals (synapses) in the CNS where Aβ peptides are generated and deposited.
Sisodia and his colleagues generated PS1-null mice whose phenotypes suggested, for the first time, that loss of PS activity was linked to defects in Notch signaling. Moreover, he showed that PS1-deficient cells fail to generate Aβ amyloid peptides as a result of reduced intramembranous "γ-secretase" activity. In parallel, he demonstrated that levels of PS are highly regulated by limiting cellular factors and provided important information regarding the assembly, subunit interactions and enzymatic mechanism(s) of "γ-secretase" processing. Finally, Sisodia's group developed and characterized mice expressing FAD-linked variants of PS1 and APP that exhibit amyloid deposits and memory deficits. These models have been invaluable for understanding the role of environmental enrichment and exercise in modulating Aβ deposition and adult neurogenesis.
Sisodia has received several awards, including the Potamkin Prize for Alzheimer's Disease Research from the American Academy of Neurology (1997); the Metropolitan Life Foundation Award for Medical Research (1998); Presidential Special Lecturer at the Annual Society for Neuroscience Meeting in 2001 and 2006; membership in the Johns Hopkins Society of Scholars (2007); Fellow of AAAS (2008); and Foreign Fellow, National Academy of Sciences, India (2010). Sisodia has served on the scientific review and advisory committees of federal and non-federal agencies, including NLS1 (NIH) Study Section ('95-'97); Member, NIA Board of Scientific Counselors ('99-''04); and The Society for Neuroscience (SFN) Program Committee (2007-2009). He has also organized, or co-organized several Adler Symposia on Alzheimer's Disease, two Keystone Symposia, and was the co-director of the Cold Spring Harbor Neurobiology of Disease course ('97,'98). He serves on the editorial boards of eight journals, including Neuron and Cell and Neurobiology of Disease, and is a member of the Dana Alliance for Brain Initiatives.