2016 Parseghian Conference

Westin La Paloma Resort & Spa – Tucson, Arizona

NPC scientists and families were delighted to return to Tucson in June for the annual Ara Parseghian Medical Research Foundation Annual meeting.  This past year has brought several major breakthroughs in our understanding of the function of NPC1 protein, and three laboratories presented these discoveries as part of the conference program.  Scientists and families were also briefed on the latest progress from hydroxypropyl beta-cyclodextrin clinical trials.

NPC disease is due to mutations in two proteins, NPC1 and NPC2; 95% of NPC patients have mutations in NPC1.  This year, two labs described their success in determining the molecular structure of NPC1 protein using different biophysical techniques.  Dr. Xiaochun Li and Günter Blobel from Rockefeller University in New York City used a method called X-ray crystallography to discover the structure of most of the NPC1 protein with a high level of molecular detail; Dr. Nieng Yan from Tsinghua University in Beijing used another method called cryo-electron microscopy to discover the structure of a greater proportion of the protein, but with slightly less detail.

The structures are very similar. The first part of the NPC1 protein, called the N-terminal domain, can pick up cholesterol—Yan and colleagues showed that this domain connects to the rest of NPC1 by a flexible linker.  Dr. Li’s crystal structure revealed a possible region of the molecule that sits in the membrane and may bind cholesterol directly.   These structural advances provide new ideas that can now be tested in terms of precisely how NPC1 transports cholesterol and how this process fails in NPC disease.

In addition, Dr. Feiran Lu, from the lab of Drs. Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical School in Dallas, showed that a small molecule called U18666A is a direct inhibitor of NPC1 protein in cells.  This finding is important for scientists because it means we can use this molecule to study NPC1 function, with a tool that enables us to turn it on and off, by simple addition or removal of this molecule.  Remarkable about all of this research progress is that three Nobel prize winners are involved—Drs. Blobel, Brown and Goldstein.

The conference was crowned by the presentations from Dr. Denny Porter from the National Institutes of Health, and Dr. Ben Machielse from Vtesse, who gave attendees up to date progress reports on cyclodextrin trials.

All of us look forward to reconvening next year from June 3-6, 2017 in Tucson, with the hope that progress in both understanding and treating NPC disease will have continued to move forward in the best ways possible to help the children and families facing NPC disease.