NIH researchers uncover how neurons die in Niemann-Pick disease type C1

Experimental drug targets cell death process and delays disease in mice

Thursday, March 17, 2016

The loss of neurons that is a hallmark of Niemann-Pick disease type C1 (NPC1) appears to result from a cell death process called necroptosis, according to a new study from the National Institutes of Health (NIH). By blocking necroptosis, it may be possible to delay onset of the disease.

NPC1 is a rare genetic disorder that primarily affects children and adolescents, causing a progressive decline in neurological and cognitive functions. It occurs when cells are unable to process cholesterol, causing a buildup that eventually leads to cell death and organ damage. Although the loss of neurons causes many NPC1 symptoms, the biochemical events leading up to neuron death was unknown until the current study.

Researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) studied skin cells from NPC1 patients enrolled in an NIH clinical trial and from a mouse model of the disease. They found that the cells die at rates faster than healthy cells, and they die by necroptosis, a form of inflammatory cell death seen in other neurodegenerative diseases. Cell death rates also were higher in samples from NPC1 patients with more severe neurological symptoms.

In laboratory studies, the researchers treated the skin cells of NPC1 patients with necrostatin 1 (Nec1), an experimental drug that blocks RIP1, a protein that carries out necroptosis inside cells. Nec1 not only delayed cell death in human NPC1 cells, it also slowed disease progression in a NPC1 mouse model.

The study authors emphasized that necroptosis is a late, if not final step, in NPC1, so blocking necroptosis likely will be only one part of a combination of therapies for the disease. Translating the findings to clinical trials will require additional laboratory work. The study authors also plan to test other necroptosis inhibitors. They suspect that this class of drugs may be effective against other diseases similar to NPC1 (known collectively as lysosomal storage disorders).

The study received additional funding from NIH’s National Center for Advancing Translational Sciences and National Heart, Lung, and Blood Institute, and the Ara Parseghian Medical Research Foundation.

Forbes D. Porter, M.D., Ph.D., NICHD Clinical Director and study author, is available to discuss the findings.

To arrange an interview with Dr. Porter, please call Linda Huynh at 301-496-5133, or e-mail

Cougnoux A, Cluzeau C, Mitra S, Li R, Williams I, Burkert K, Wassif CA, Zheng W, and Porter FD. Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target. Cell Death and Disease DOI: 10.1038/CDDIS.2016.16 (2016).


Learn about NPC1 research at NICHD, including interviews with Dr. Porter and families participating in clinical research.

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About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s website at  

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

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