Blair Lab

Running, talking, breathing, remembering…

These things are coordinated by thousands of different proteins at work in our cells. Among them is a group of sentinels called chaperones that ensure the propriety of the majority of cellular proteins and resultant cellular functions. Our lab is focused on the role of chaperones in a group of more than 15 neurological degenerative diseases collectively termed “tauopathies”, the most common being Alzheimer’s disease. We hope that an understanding of chaperone function will enable therapeutic strategies that increase quality of life, halt disease progression and ultimately cure neurodegenerative diseases. 

Research Overview

Our lab is focused on preserving brain health through the regulation of the cell’s natural defense system, the molecular chaperone network. This network gets out of balance through aging and disease, which contribute to neuropsychiatric disorders like post-traumatic stress disorder (PTSD) and Alzheimer’s disease. Our group is systematically interrogating how specific chaperones preserve or destroy protein aggregates in Alzheimer’s disease and how the balance of one particular chaperone, FKBP51, impacts stress response for stress-related mental health disorders. In addition to expanding our knowledge about the biology and identifying targets, we are working to develop therapeutics to restore the balance through the regulation of molecular chaperones and therefore preserve brain health at the same time. We are confident that this strategy will yield tractable therapies to halt or possibly reverse Alzheimer’s disease progression as well as help reduce symptoms associated with PTSD and depression.

Learn more about our research

Laura Blair

PhD

Principal Investigator and Associate Professor

Meet the Team

Latest News

Featured Publications

  • Jiang, Lulu, Pijush Chakraborty, Lushuang Zhang, Melissa Wong, Shannon E Hill, Chelsea Joy Webber, Jenna Libera, Laura J Blair, Benjamin Wolozin, and Markus Zweckstetter. (2023) 2023. “Chaperoning of Specific Tau Structure by Immunophilin FKBP12 Regulates the Neuronal Resilience to Extracellular Stress.”. Science Advances 9 (5): eadd9789. https://doi.org/10.1126/sciadv.add9789.

    Alzheimer's disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa FK506-binding protein (also known as FKBP prolyl isomerase 1A), regulates the neuronal resilience by chaperoning a specific structure in monomeric tau. Using a combination of mouse and cell experiments, in vitro aggregation experiments, nuclear magnetic resonance-based structural analysis of monomeric tau, site-specific phosphorylation and mutation, as well as structure-based analysis using the neural network-based structure prediction program AlphaFold, we define the molecular factors that govern the binding of FKBP12 to tau and its influence on tau-induced neurotoxicity. We further demonstrate that tyrosine phosphorylation of tau blocks the binding of FKBP12 to two highly specific structural motifs in tau. Our data together with previous results demonstrating FKBP12/tau colocalization in neurons and neurofibrillary tangles support a critical role of FKBP12 in regulating tau pathology.

  • Gebru, Niat T, Shannon E Hill, and Laura J Blair. (2023) 2023. “Genetically Engineered Mouse Models of FK506-Binding Protein 5.”. Journal of Cellular Biochemistry. https://doi.org/10.1002/jcb.30374.

    FK506 binding protein 51 (FKBP51) is a molecular chaperone that influences stress response. In addition to having an integral role in the regulation of steroid hormone receptors, including glucocorticoid receptor, FKBP51 has been linked with several biological processes including metabolism and neuronal health. Genetic and epigenetic alterations in the gene that encodes FKBP51, FKBP5, are associated with increased susceptibility to multiple neuropsychiatric disorders, which has fueled much of the research on this protein. Because of the complexity of these processes, animal models have been important in understanding the role of FKBP51. This review examines each of the current mouse models of FKBP5, which include whole animal knockout, conditional knockout, overexpression, and humanized mouse models. The generation of each model and observational details are discussed, including behavioral phenotypes, molecular changes, and electrophysiological alterations basally and following various challenges. While much has been learned through these models, there are still many aspects of FKBP51 biology that remain opaque and future studies are needed to help illuminate these current gaps in knowledge. Overall, FKBP5 continues to be an exciting potential target for stress-related disorders.