Aging Brain Seminar with Jerold Chun, MD, PhD

Genomic mosaicism and somatic gene recombination in the normal and Alzheimer’s disease brain

Speculations that somatic DNA sequence changes might underlie the brain’s elaborate cellular diversity and organization co-emerged in the 1960s with antibody diversity-generating mechanisms that were first demonstrated by S. Tonegawa through V(D)J recombination in the mid-1970s. Efforts to identify an analogous form of gene recombination in the brain that began at MIT in the late 1980s, were not clarifying. However, these efforts identified genomic mosaicism – wherein each brain cell genome is distinct in its DNA sequence – and indicated that focusing on single or a few cells harboring a mosaically recombined gene might enable its detection, especially if a candidate existed. Such a candidate emerged in the Alzheimer’s disease gene Amyloid Precursor Protein (APP). Evidence for APP somatic gene recombination (SGR) in human neurons will be presented: SGR is distinct from immunological recombination and involves reverse transcriptase activity to synthesize “genomic cDNAs” that lack introns, which may represent a more ancient process by analogy to forms of recombination in yeast and evolutionary processed pseudogenes, but occurring somatically in the human brain. Implications for normal brain function and Alzheimer’s disease will be discussed.

Jerold Chun, MD, PhD, is Professor and Senior Vice President of Neuroscience Drug Discovery at Sanford Burnham Prebys Medical Discovery Institute (SBP). He received his MD and PhD degrees (Neuroscience; with C.J. Shatz) through the Medical Scientist Training Program at Stanford University School of Medicine. He moved east as a Helen Hay Whitney Postdoctoral Fellow to the Whitehead Institute for Biomedical Research, MIT (with R. Jaenisch and D. Baltimore). Dr. Chun then joined the faculty at the UCSD School of Medicine, where he became Professor of Pharmacology and Neurosciences and directed the Neurosciences Graduate Program. He subsequently became Department Head of Molecular Neuroscience at Merck Research Laboratories before returning to academia as Professor at The Scripps Research Institute and adjunct Professor at UCSD, before his current position. He has made important contributions to our understanding of the brain and its diseases. His lab identified genomic mosaicism and somatic gene recombination within the brain and its involvement in the most common forms of Alzheimer’s disease, with relevance to other brain diseases. In separate work, his lab also identified the first lysophospholipid receptor, an initial member of a growing family of lipid receptors that includes S1P receptors that are targets for two current neuroscience medicines (fingolimod & siponimod for Multiple Sclerosis) with lysophospholipid receptors also linked to other diseases, including hydrocephalus, schizophrenia, neuropathic pain and fibrosis. Dr. Chun has authored more than 300 scientific publications, has been recognized in Thomson Reuters’ World’s Most Influential Scientific Minds citation list, and is a member of numerous advisory, review, and editorial boards in both academia and industry.

Host

Elly Nedivi

Organizer

Brittany Greenough