Niemann-Pick type C (NPC) disease is a cholesterol-glycosphingolipid (GSL) lysosomal storage disorder caused by defects in the NPC1 or NPC2 proteins, both of which are implicated in the trafficking of cholesterol and other compounds out of lysosomes. Most affected individuals appear normal at birth, develop behavioral changes and progressive impairment of motor and intellectual function in the first decade of life, and succumb to the disease in their second decade. Few effective treatments are currently approved and pathogenic mechanisms leading to brain dysfunction are poorly understood. One well documented feature of NPC disease that is believed to contribute to the progressive ataxia in humans and animal models is early death of Purkinje cells (PCs). But why these cells die so early has never been explained. We have proposed that PC vulnerability is a result of the formation of swellings or spheroids along the axons of these neurons. Also known as neuroaxonal dystrophy (NAD), this phenomenon has been reported in a wide variety of lysosomal diseases as well as in other commoner neurodegenerative diseases like Alzheimer's. It has been proposed to be a major contributor to clinical neurological dysfunction, yet it is rarely studied. Importantly, of all lysosomal diseases in which NAD has been described, it is NPC disease in which the scale and frequency of its occurrence is most excessive with axons of PCs being particularly susceptible. Axonal spheroids in NPC disease contain localized accumulations of mitochondria, dense bodies, tubulovesicular and endosomal/retrosomal-like profiles and possible autophagosomes, all of which are suggestive of compromise in axoplasmic transport. The goal of the current study is to use Npc1-/- mice and Npc1-/- mice with inherently fluorescent Purkinje cells (L7-GFP Npc1-/- mice) in a series of in vivo and in vitro experiments to characterize the constituents of axonal spheroids and determine the dynamic features of spheroid development throughout the course of the disease. We will test hypotheses focused on the relationship between NAD and PC death, and test the ability of several drugs (miglustat, cyclodextrins and selected antioxidants) that have shown efficacy in the NPC mouse model to modify the formation of spheroids. Understanding why NAD occurs, what its relationship is to the lysosomal defect in PCs, and what it takes to prevent or reverse its development, are critical issues for treatment of NPC disease. Moreover, understanding mechanisms that connect axonal pathology and defective axonal transport to the rest of the NPC pathogenic cascade may provide insights into more common neurological diseases like Alzheimer's where axonal pathology is increasingly recognized.

Public Health Relevance

Niemann-Pick disease type C (NPC) is a fatal genetic disorder of the brain that affects children. Like other rare diseases (7000 of which are now recognized by the NIH), NPC occurs worldwide - it is panethnic - and occurs at a frequency of 1:120,000 births. While normal appearing at birth, affected individuals develop severe, progressive brain disease and generally die in their second decade. Few treatments are available and even the pathogenic process leading to brain dysfunction and death are poorly understood. The goal of this proposal is to test innovative hypotheses addressing why neurons die prematurely in this disorder. The focus here is on a special type of axonal pathology (neuroaxonal dystrophy or NAD) known to accompany NPC and other brain diseases but rarely investigated as a contributor to neuron death. Yet NAD is increasingly recognized as a feature in other neurodegenerative diseases like Alzheimer's. Understanding why it occurs, what its role is in neuron death, and how it is influenced by emerging therapeutic agents will provide important contributions to understanding and treating NPC disease, and may give new insights into how to address similar issues in commoner disorders like Alzheimer's.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
International Research Fellowships (FIC) (F05)
Project #
Application #
Study Section
NST-2 Subcommittee (NST)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Schools of Medicine
United States
Zip Code
Micsenyi, Matthew C; Sikora, Jakub; Stephney, Gloria et al. (2013) Lysosomal membrane permeability stimulates protein aggregate formation in neurons of a lysosomal disease. J Neurosci 33:10815-27