Epigenetic modifications, such as histone acetylation, are dysregualted in Alzheimer’s disease (AD) and other neurodegenerative disorders, resulting altered patterns of neuronal gene expression and cognitive decline. In this episode, Eva Benito-Garagorri reveals that the small molecule histone-deacetylase (HDAC) suberoylanilide hydroxamic acid (SAHA) improves cognitive function and restores neuronal gene expression patterns in murine models of aging and neurodegeneration. Importantly, oral administration of SAHA provided these beneficial effects in neurons and did not affect non-neuronal cells. The results of this study suggest that SAHA should be further explored for the treatment of neurodegenerative disorders and age-related cognitive decline.
An inability to properly sustain blood cell production results in the development of hematopoietic disorders. Epigenetic regulators have been shown to be involved in the function of hematopoietic stem and progenitor cells; however, dysfunction of these enzymes is associated with development of malignancies. In this episode Stephen Nimer and colleagues identify the type II arginine methyltransferase PRMT5 as an important regulator of adult hematopoiesis. Mice lacking PRMT5 developed fatal pancytopenia due to reduced proliferation of hematopoietic progenitor cells as the results of impaired cytokine signaling and increased p53 signaling. Hematopoietic stem cell populations were not initially reduced in these animals; however, this population was unable to restore blood cell populations in lethally irradiated mice. Together, the results of this study provide important insight into the role of PRMT5-mediated gene expression in maintaining hematopoietic homeostasis.
Group A Streptococcus (GAS) causes a wide array of infections ranging from mild to serious and even life threatening. Epidemic strains of GAS have enhanced virulence; however, the molecular events that allow for widespread dissemination of this disease are not fully understood. In this episode, James Musser discusses the identification of genetic changes that cause increased virulence in epidemic strains of GAS. Extensive genomic sequencing of pre- and post-epidemic strains revealed the presence of SNPs within a regulatory element that increase the expression of two potent bacterial toxins. The results of this study provide insight into the molecular drivers of the emergence of epidemic GAS strains.
Dr. Stuart Kornfeld is the David C. and Betty Farrell Distinguished Professor of Medicine at Washington University in St. Louis. He is best known for his work elucidating the processes governing lysosome biogenesis. His research continues to uncover roles for oligosaccharide biosynthesis, processing, and maturation in mediating proper folding and transport of proteins. In an interview with JCI Editor-at-Large Ushma Neill, Kornfeld discusses how his first biochemistry course, taught by Carl and Gerty Cori, and his work as a postdoctoral researcher in Luis Glaser’s lab led to his interest in the role of sugar moieties in cellular physiology. Kornfeld also discusses his early work with postdoctoral fellows Ira Tabas and Ajit Varki and graduate student Marc Reitman in characterizing the trafficking of lysosomal proteins. Finally, Kornfeld addresses the importance of mentors in the development of physician-scientists.
Ebola virus causes severe hemorrhagic fever and is readily transmitted through contact with or inhalation of aerosolized biological fluids from infected individuals. Vaccines against this deadly virus are currently in development. As Ebola outbreaks often occur in areas of Africa that lack infrastructure and trained medical personal, development of a needle-free vaccine would be advantageous. In this episode, Alexander Bukreyev and Michelle Meyer discuss their work, which demonstrates that an aerosolized formulation of an Ebola vaccine protects rhesus macaques from infection. The aerosolized version of the vaccine elicited an Ebola-specific response that was on par or better that an injected, liquid form of the same vaccine. Importantly, a single vaccination with the aerosolized formulation conferred 100% protection to macaques exposed to a lethal dose of Ebola virus. Together, these results support evaluation of the aerosolized vaccine formulation in clinical trials.