Boyer, David
David is a student in the Biochemistry, Molecular and Structural Biology Graduate Program, where he works in the laboratory of Dr. David Eisenberg. He joined the CMB training program in 2016. He received a B.S. degree in 2014 from the University of Michigan.
Mentor: Dr. David Eisenberg
First described by Alois Alzheimer over 100 years ago, Alzheimer’s Disease (AD) is simultaneously well studied, yet poorly understood. The amyloid theory of AD posits that misfolded or improperly cleared amyloid-ß (Aß) leads to interneuronal toxic plaques, promoting cell death. However, more recently, attention has turned to the microtubule-associated protein tau as the possible causative agent in AD. Normally involved in stabilizing microtubules, tau isoforms are the major component of neurofibrillary tangles (NFTs). NFTs are aggregates of filamentous tau polymers located within cell bodies that comprise a portion of the fibrillary pathologies of AD. Many laboratories have elucidated important factors that affect the transition from functional tau to fibers such as hyper-phosphorylation, truncation, and alternative splicing of tau. However, there are many questions that remain to be resolved. What is the toxic conformation of tau in AD? What sequence and structural elements govern the ability of tau to seed formation of fibers from monomeric tau? Can tau fibrils be seeded by other amyloids? What are the atomic structures of functionally relevant tau isoforms?
Adding to the difficulty of understanding tau’s role in the pathology of AD is the fact that tau is an intrinsically disordered protein (IDP). IDPs can adopt numerous conformations and binding partners, making a cohesive picture of their structure-function relationship elusive. I hypothesize that applying an approach termed deep mutational scanning (DMS) to tau can help overcome this problem. DMS harnesses the power of next-generation sequencing and high-throughput functional screening to map sequence-function relationships. By coupling the generation of a large library of tau variants to a high-throughput functional screen (e.g., aggregation, microtubule binding), aDMS would provide both critical insight into the sequence-function relationship and aid in identifying important residues / structural motifs for further structural and drug design efforts. In addition, I plan to employ cryo-electron microscopy (for large MW complexes, i.e. fibers), traditional X-ray crystallography (for medium MW constructs, e.g., tau in complex with interacting proteins), as well as micro-electron diffraction techniques (for small MW peptides recalcitrant to X-ray crystallography), to elucidate atomic models of tau in its various states.
