When people hear of high cholesterol or low cholesterol, it usually refers to the amount of cholesterol in the blood. Cholesterol (and similar lipids) are also found inside the cells where it is broken down into fatty acids for the cell to use. Some cholesterol is stored in the cell membrane for future use, some is used to create steroids and bile acids, and the excess is transported out of the cell.
With Niemann-Pick Type C, the excess cholesterol cannot be removed and it builds up inside the cell. Given enough time, the accumulation will smother the cell. This occurs primarily in the liver, spleen, and central nervous system. In the liver and spleen, the accumulation cause the organs to swell and may lead to liver failure, particularly in infancy.
While cell death occurs in the brain and central nervous system, a second problem is also present. Cholesterol is necessary to the creation of glycolipids that are critical to nerve development and function. With Niemann-Pick Type C, the series of reactions necessary to form these chemicals fails to take place at an unknown point in the sequence. As a result, neuron function may decline long before the cell itself dies.
Why is NPC so devasting?
Researchers believe the metabolic processes affected by Niemann-Pick Type C are both very basic and very critical. While most metabolic processes differ among various species (reptiles, fish, and mammals all function very differently), forms of NPC have been identified in many species, including humans, cats, mice, worms, and yeast. Other metabolic processes that are common among species are part of the basic biological foundation for life.
In addition to being common among species, the metabolic process appears throughout an individual but is expressed in different ways. The biochemical effect of NPC on the brain and central nervous system is different than the effect on the liver and spleen which is different than the effect on other cells.
Finally, the number and relatively small size of the genetic mutations indicates that any disruption has a significant impact on the organism. Genes mutate frequently, but most mutations have no effect - they are either harmless (like an unusal eye color) or are offset by other genes performing similar tasks correctly. With NPC, any mutation is more likely to disrupt an important process.
All of these factors make identifying the biochemical processes involved a complex task. Scientists have learned how cholesterol enters the cell and becomes part of the endosome, how it is broken down by lysosomes, and how it is processed by the endoplasmic reticulum. They have not been able to identify how cholesterol moves between endsosomes, lysosomes, and the endoplasmic reticulum - the very activity affected by Niemann-Pick Type C.
New research helps
Recent research has begun to shed light on the functions of Niemann-Pick genes but has also raised even more questions. NPC1 has now been identified as a transmembrane protein (embedded in the wall of the lysosome) and been shown to act as a transport mechanism. However, the NPC1 protein does not appear to transport cholesterol directly.
A second gene, HE1 (formerly called NPC2), does bind with cholesterol but appears to operate at a different point in the metabolic process. HE1 is a soluble protein that can move within the lysosome (and may move outside the lysosome as well). The failure of either NPC1 or HE1 leads to Niemann-Pick Type C.
The research is a major step forward but more work is needed to fully understand the complete biochemical process. Questions have been raised as to whether the excessive cholesterol storage is the direct result of NPC or if excessive storage of gangliosides (another similar lipid) is the direct result and the cholesterol problem is a secondary effect.
On the following pages, the general process of cholesteral metabolism is shown for normal cells and for Niemann-Pick Type C cells.
