David R. Borchelt, Ph.D.
Professor of Neuroscience
Director, SantaFe Health Alzheimer’s Disease Research Center
Investigator, McKnight Brain Institute & CTRND
Department of Neuroscience
Center for Translational Research in Neurodegenerative Disease
1275 Center Drive
PO Box 100159
Gainesville, FL 32610-0159
Key Words: Alzheimer’s Disease; Huntington’s Disease; Amyotrophic Lateral Sclerosis; Neurodegeneration; Protein Misfolding
My laboratory is focused on defining the basic molecular events that underlie human neurodegenerative diseases, such as Huntington’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease. Over the past several years there has been tremendous progress in identifying the gene defects that cause inherited forms of these diseases, which are progressive, fatal disorders that result from the dysfunction and death of specific populations of nerve cells. In each case, a mutation in a specific gene causes a change in the amino acid sequence of a specific protein to initiate a cascade of events that lead to disease. The end result of this cascade is the accumulation of misfolded proteins or peptides in regions of the CNS affected by each disease to cause unique pathologic lesions. As we have begun to decipher the mechanisms of these diseases, we have found common features in these diseases that implicate common pathways. These commonalities offer hope that we will identify therapies that will be broadly beneficial in many neurodegenerative conditions, including many of the rare neurodegenerative diseases. In parallel, we seek to identify processes that are unique to a particular disease and thus of high value as therapeutic targets to ameliorate symptoms that are specific to each of these disorders.
Research Focus & Aims:
My laboratory has been committed to investigations designed to elucidate the molecular processes by which specific mutant proteins adopt disease-specific conformations and to define the mechanisms by which these altered proteins lead to the dysfunction and death of specific populations of nerve cells. This work involves the use of transgenic mouse models, in which the introduction of mutant human genes elicits a disorder that resembles the human disease; knockout mice, where the loss of a specific gene may alter the clinical or pathological appearance of the disease; and cell culture systems to examine the effect of mutations on the function and biology of the mutated proteins. Collectively, these approaches provide insight into the molecular mechanisms of disease and have the potential to identify new therapeutic strategies for these disorders.
I have been with the University of Florida since April of 2005 after 13 years on the faculty of Johns Hopkins University School of Medicine. I was recruited to the McKnight Brain Institute of UF to direct research in Alzheimer’s disease that has been generously funded by an endowment from SantaFe HealthCare (a division of AvMed, Inc.). I have authored, or co-authored, more than 160 research papers focusing on human neurodegenerative disorders. I received my Ph.D. from the University of Kentucky in 1986 where I studied the viruses that are similar to the virus that causes AIDS. After receiving my doctorate, I worked as a post-doctoral fellow with Dr. Stanley Prusiner at the University of California in San Francisco. In 1999 Dr. Prusiner won the Nobel Prize in Medicine for his work on infectious proteins that cause Mad Cow disease, Cruetzfeldt-Jakob disease, and other neurodegenerative diseases of animals and humans. The prion hypothesis is built upon the notion that a brain protein can acquire a conformation (a 3-dimensional shape) that then serves as a template to replicate the conformation; essentially transmitting the conformation from one protein to the next. During my time with Dr. Prusiner, I produced some of the seminal work on prion protein that supported this hypothesis. From this work, I began to realize that most human neurodegenerative diseases, including amyotrophic lateral sclerosis, Huntington’s disease, and Alzheimer’s disease, share similarities with prion disease in that the symptoms and pathology are caused by the accumulation of proteins in altered conformations.