Scott Waldman, MD, PhD
Name of Institution:
Thomas Jefferson University, Philadelphia, PA
Targeting GUCY2C for Neuroprotection in Experimental Parkinson’s Disease
Dr. Scott Waldman obtained his PhD degree from Thomas Jefferson University, and his MD degree from Stanford University in Stanford, CA. He was a fellow at Stanford University in the laboratory of Dr. Ferid Murad, who won the 1998 Noble Prize in Physiology or Medicine. Dr. Waldman is currently the Samuel MV Hamilton Professor of Medicine and Chair of Pharmacology, Physiology, and Cancer Biology at Thomas Jefferson University. He is a member of numerous professional boards and editor of numerous peer-reviewed journals. He has mentored dozens of junior faculty, post-doctoral fellows, and students. He is the author of hundreds of papers, and more than 100 patents/applications. He has established three companies, all with assets in clinical development. Dr. Waldman’s research focuses on novel diagnostic, prevention, and therapeutic strategies for patients with cancer, obesity, or neurodegenerative diseases.
To determine if GUCY2C activation by linaclotide can block brain cell toxicity in PD.
Parkinson’s disease (PD) pathology is associated with an inadequacy of mitochondria, the energy or adenosine triphosphate (ATP)-producing powerhouses of cells. A decrease in the amount of ATP produced, along with an accumulation of mitochondrial waste products may contribute to cell death in PD. These insights suggest that developing new therapies that enhance mitochondrial function in brain cells may be a strategy to prevent or slow down progression of PD. Recently, high concentrations of the protein GUCY2C were discovered in PD brain cells. GUCY2C is best known as a receptor found on cells in the intestine, where it regulates water secretion. The drug linaclotide, which activates GUCY2C and increases intestinal water secretion, is FDA-approved to treat constipation. Importantly, GUCY2C also drives the generation of mitochondria in the intestine and our preliminary studies revealed that genetically silencing GUCY2C in brain cells in mice reduces their ability to make mitochondria and is associated with neurodegeneration. In this study we will determine if GUCY2C activation by linaclotide can prevent the death of brain cells.
We will activate GUCY2C in brain cells using linaclotide and determine whether this increases their ATP production and reduces their toxic waste products. Also, we will test whether this enhanced mitochondrial capacity produced by the linaclotide-GUCY2C axis can prevent the death of brain cells. Finally, we will test the therapeutic utility of linaclotide to prevent neurodegeneration in a mouse-model of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Proposed studies seek to define a new mechanism in which activation of GUCY2C by linaclotide promotes mitochondria function and potentially prevents neurodegeneration. Because linaclotide is already FDA-approved, these studies could be rapidly translated into new therapeutic strategies for PD.