Sexually reproducing organisms employ a specialized developmental program to generate cells that are used to pass genetic material from one generation to the next. These reproductive cells, called gametes, contain half the DNA complement of a typical cell and are known to us as sperm, eggs, pollen, and spores etc. A hallmark feature of gamete development is a marked decrease in mRNA production (i.e. transcriptional control) and a concurrent emphasis on genetic regulation at the level of protein synthesis (i.e. translational control). We discovered that in order to control translation during gamete development, budding yeast builds massive RNA-binding protein structures that exhibit biochemical properties of amyloid (thus termed ‘amyloid-like’). Our research goals are to discover and understand the pathways and mechanisms by which cells regulate formation, function, and reversibility of amyloids. We strive to expand our understanding of birth defects and fertility while also providing key insights into principles underlying neurodegenerative disease.
Amyloids are fibrous protein aggregates that are predominantly understood for their roles in the etiology of neurodegenerative diseases including Alzheimer’s, Parkinson’s, and prion diseases. What is remarkable about amyloid-like assemblies in yeast is that they are not pathogenic- on the contrary they are both functional and regulated. These structures bind to and repress translation of key transcripts and are essential for gamete production. Formation of these repressors is regulated by starvation and clearance is regulated by precise developmental cues. Regulated amyloid-like assemblies are also features of mouse and frog meiosis highlighting their evolutionary conservation and likely ancient evolutionary origin in sexual reproduction.
Our lab employs genetic, cell biological, and biochemical approaches to understand the pathways and mechanisms underlying formation and clearance of amyloid-like assemblies. We also use a combination of in vitro and in vivo approaches to decipher how translation can be regulated by this intriguing class of RNA-binding structures. We are also using yeast to screen and identify compounds that prevent and/or disassemble amyloid-like assemblies. The compounds that we identify in this manner will be excellent potential therapeutics for neurodegenerative disease. Lastly, we are investigating the hypothesis that mammalian sperm development also relies on amyloid-like assemblies to regulate gene expression.
Our studies will lay the foundation for understanding the molecular underpinnings of how cells regulate and process amyloid-like assemblies. Each finding provides the potential lead to a pathway or gene that could be a therapeutic target. Despite much research and development, anti-amyloid preventative therapies have been elusive. They are needed for neurodegenerative diseases in which few if any effective preventative therapies are currently available. Therapeutic strategies resulting from this work will rely on my ability to apply the findings we gain from this study to neurodegenerative disease models. Columbia University Medical Center and the Taub Institute for Alzheimer’s and Aging Research provide the supportive framework and collaborative opportunities to make this possible.