Andrey Tsvetkov

G-quadruplexes in the brain DNA and RNA sequences containing four stretches of guanines are able to form tetra-stranded stable structures called the G-quadruplex (G4-DNA and G4-RNA). Although G4-DNA and G4-RNA have been studied in vitro for years, it is now clear that these structures are controlled by various G4-binding proteins and play important roles in DNA replication, transcription, and RNA processing in vivo. In the lab, we investigate whether manipulating G4-DNA and G4-RNA pathways could be a new target for treatment of neurodegenerative diseases and slowing aging. Molecular mechanisms of neuronal autophagy Abnormal intracellular protein deposits and damaged organelles characterize many neurodegenerative disorders. Neurons are less able to degrade abnormal proteins and damaged organelles as they become older, linking the build-up of protein deposits and organelles and the appearance of adult-onset neurodegenerative disorders. We focus on the physiological and pathophysiological functions of macroautophagy (often called autophagy) in age-associated neuronal dysfunction and neurodegeneration. Our studies strongly suggest that at least some autophagic pathways can be modified with autophagy enhancers to boost degradation of abnormal protein, resulting in improved neuronal health. Transcriptional dysregulation in brain aging Epigenetic mechanisms, such as chemical modifications of DNA or associated proteins, are important in modulating gene transcription and, as a result, in regulating mechanisms of healthy and pathogenic aging. Phospholipids are abundant within the interior of the nucleus, but their function is not clear. Our data suggest that phospholipids target many proteins in the neuronal nucleus that epigenetically control transcription and DNA homeostasis. The goals of this project are to uncover fundamental molecular mechanisms by which phospholipids transcriptionally regulate successful and unsuccessful aging. Chemotherapy- and virus-induced brain damage and aging The degenerative processes induced by some chemicals or neurotropic viruses are remarkably similar to processes in aging. Thus, the mechanisms by which neurons cope with a chemical or viral insult may be a useful model of natural aging. Understanding the common mechanisms in chemically or virally associated neurological disturbances and aging can produce insights into our understanding of aging in general. The goals of this project are to understand molecular mechanisms by which chemotherapy drugs and neurotropic viruses induce neuronal dysfunction and accelerated aging.