Gary Ho, MD, PhD 

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Investigator Bio:

Dr. Ho is an Associate Neurologist at Brigham and Women’s Hospital and an Assistant Professor of 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 alpha-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. In pursuit of this goal, there are three main avenues of investigation in Dr. Ho’s lab. These include 1) the role of fatty acid protein modification (palmitoylation) in the biology of alpha-synuclein, 2) modulating palmitoylation of trafficking proteins as a therapeutic strategy in PD, and 3) synaptic functions of alpha-synuclein. Dr. Ho is a previous recipient of APDA’s George C. Cotzias Fellowship. 

Objectives/Background:

In PD, excess of a protein called alpha-synuclein interferes with the movement of materials inside brain cells. In contrast, we have previously found that increasing protein palmitoylation can restore transport function within a cell. Palmitoylation is the modification of proteins, many of which are involved in transport, by the fatty acid palmitate. We previously identified the protein LIMP2 as a key palmitoylated candidate to target for PD treatment. This is because LIMP2 is the trafficking receptor for glucocerebrosidase (Gcase), an enzyme in the cell’s recycling center (lysosome). The gene that encodes Gcase, GBA1, is the most common genetic risk factor for PD. LIMP2 transports GCase to the lysosome, a component of the cell which can break down and dispose of excess alpha-synuclein. In this proposal, we will first determine if our newly identified palmitoylation of LIMP2 can fix abnormal transport of GCase in PD patient stem cell-derived brain cells. Next, we will evaluate if palmitoylation of LIMP2 can reduce abnormal disease-associated forms of alpha-synuclein. 

Methods/Design:

To answer our experimental questions, we will employ brains cells grown in the lab from reprogrammed skin or blood cells initially isolated from patients with the L444P mutation in the GBA1 gene encoding glucocerebrosidase (GCase). Individuals who harbor this mutation in one of the two copies of their GBA1 genes are at higher risk of PD and also typically have a more severe disease course. In Aim 1, we will introduce either normal LIMP2 or a mutant of LIMP2 which cannot be palmitoylated and assess GCase transport through the brain cells. (The L444P mutation normally impairs the transport of GCase). In Aim 2, we will use the same experimental setup to determine if palmitoylation of LIMP2 can reduce abnormally high levels of the protein alpha-synuclein. 

Relevance to Diagnosis/Treatment of Parkinson’s Disease:

This proposal will advance our knowledge of how the basic cell process of palmitoylation – when a protein gets a fatty acid attachment – is involved in PD pathology. Our prior work showed the potential of altering fatty acid attachment to treat PD using patient-derived brain cells and animal models. In this proposal, we focus on the impact of palmitoylation in a highly relevant pathway in PD, that of Gcase and lysosomal function. By exploring the therapeutic potential of increasing palmitoylation of LIMP2, the GCase trafficking receptor, we will gain knowledge critical to the development of new treatments that work by adjusting this fatty acid process for PD.