Wade Harper, PhD
Bert and Natalie Vallee Professor of Molecular Pathology and Chair of the Department of Cell Biology
Neurons are the substrate of our cognition, memory, and emotion. Yet, remarkably, they are also cells like any other tissue of the body, containing a nucleus, mitochondria, and proteins that ensure cells are able to make energy and survive. When neurons die, such as in Alzheimer’s disease (AD), patients have impairments in cognition and behavior. Postmortem brain samples have shown that neurons in patients’ brains exhibit extensive plaques (aggregates comprised of particular proteins that litter the brain). Scientists and clinicians have theorized that the presence of these aggregates is toxic to neurons and obstruct normal cell function, ultimately leading to degeneration and death of neurons. Therefore, to understand what leads to neurodegeneration, it is essential to look deep inside neurons to watch—and ultimately understand—their basic protein organelle and housekeeping systems.
All cells of the body, including neurons, rely on proteins to keep them alive. For example, the metabolic enzymes that create energy for your cells to work are, in fact, proteins. Where particular proteins reside inside of the cell (e.g., mitochondria, nucleus) determines how they will ultimately function. My lab focuses on understanding the underlying cell biology of neurons by concentrating on protein sorting and organelle trafficking and by examining how and when particular proteins and organelles find their ultimate destination. In addition, we study how individual organelles such as mitochondria are maintained in a healthy form via quality control pathways.
The importance of protein trafficking is exemplified by one particular protein, amyloid precursor protein (APP). When APP encounters certain enzymes, it is processed into various fragments, one of which is called amyloid-beta, a key component of aggregates found in AD brains. Depending on the enzyme that cuts APP, the resulting fragments can be toxic or non-toxic to cells, meaning that some fragments end up being normally recycled, while other fragments end up aggregating into toxic plaques. Critically, specific enzymes that cut APP are located in particular parts of the cell, so the decision for APP to end up in particular cellular compartments ultimately determines how APP is cut. A major focus of my laboratory is to understand the molecular process that underlies APP’s movement through the cell’s transport system as it makes its way to its ultimate destination.
Studying the processing of APP and monitoring how it is sorted is a large undertaking. To embark on these experiments, we have generated new molecular tools that enable us to measure and track proteins to various parts of the cell. We have also developed new ways of perturbing the cellular machinery that transports proteins from one part of the cell to another in order to see how APP and its fragments are localized. Using new instruments and methods, we can visualize the entire complement of proteins without bias and see the entire network of proteins in isolated organelles. We believe our work will generate one of the first quantitative maps of how APP products are sorted and trafficked around the neuron with unprecedented resolution. Moreover, by examining these processes in the context of AD-associated mutations that affect protein trafficking and processing, we believe this work will lead to a better understanding of how protein and organelle dynamics may be perturbed in AD and provide important links to other neurodegenerative diseases. Indeed, work in parallel in the lab has provided a quantitative understanding of how mitochondrial quality control pathways are linked to genes mutated in Parkinson’s disease and ALS.
By looking inside neurons and watching them work as cellular machines, we believe we will gain clues on how fundamental cellular function could provide new ways to prevent AD and other devastating neurodegenerative diseases.