Investigator:
Gary Ho, MD, PhD
Name of Institution:
Brigham and Women’s Hospital/Harvard Medical School, Boston, MA
Project Title:
Leveraging protein palmitoylation to correct vesicle trafficking defects in Parkinson’s disease
Investigator Bio:
Dr. Ho is an Associate Neurologist at Brigham and Women’s Hospital and an Instructor in Neurology at Harvard Medical School. Dr. Ho obtained his BA degree in Biochemical Sciences from Harvard College. Following this, he matriculated at the MD/PhD program at Johns Hopkins University in Baltimore, MD, where he studied nitric oxide signaling and palmitoylation of synaptic proteins under the mentorship of Dr. Solomon Snyder. Dr. Ho then completed his Neurology and Movement disorders training at Massachusetts General Hospital and Brigham and Women’s Hospital. During fellowship, he became interested in the role of the protein α -synuclein in Parkinson’s disease (PD) while conducting research in the lab of Dr. Dennis Selkoe. Currently, Dr. Ho’s clinical and research interests are in the group of neurodegenerative disorders known as synucleinopathies, which includes PD, Lewy body dementia, and others. His main long-term research goal is to understand the cell biology of these diseases so that specific targeted treatments may be developed.
Objective:
To determine whether enzymes that add the fat molecule palmitate to proteins (palmitoyltransferases) can correct vesicle trafficking defects caused by α -synuclein in PD.
Background:
α -synuclein is a key culprit in the death of neurons in PD. One reason is that when present in excess, α -synuclein sticks to the outside of vesicles, bubble-like structures that transport cargo throughout the neuron. This causes the vesicles to be misshapen and abnormally clustered. In contrast, modification of certain vesicle proteins by the fatty acid palmitate, a process known as palmitoylation, helps promote normal vesicle trafficking. Palmitoylation of vesicle-embedded proteins act as “wedges” in the membrane and help curve it into the proper spherical shape. Our goal is to leverage palmitoylation as a tool to correct vesicle structure and function in the hopes of developing a disease modifying treatment for PD.
Methods/Design:
We will use stem cell-derived neurons from a patient with inherited PD and neurons from mice with PD symptoms as our main model systems. We will introduce selected palmitoyltransferase enzymes into these cells and visualize vesicle structure and trafficking to determine if there is any improvement in these parameters.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If palmitoylation improves the structure and function of vesicles in our studies, drugs or gene therapy targeting palmitoylation may be possible new therapies for PD.