Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease

Abstract

Niemann-Pick type C is a neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, npc1 and npc2. Cells lacking Npc1, which is a transmembrane protein related to the Hedgehog receptor Patched, or Npc2, which is a secreted cholesterol-binding protein, have aberrant organelle trafficking and accumulate large quantities of cholesterol and other lipids. Though the Npc proteins are produced by all cells, cerebellar Purkinje neurons are especially sensitive to loss of Npc function. Since Niemann-Pick type C disease involves circulating molecules such as sterols and steroids and a robust inflammatory response within the brain parenchyma, it is crucial to determine whether external factors affect the survival of Purkinje cells (PCs). We investigated the basis of neurodegeneration in chimeric mice that have functional npc1 in only some cells. Death of mutant npc1 cells was not prevented by neighboring wild-type cells, and wild-type PCs were not poisoned by surrounding mutant npc1 cells. PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. Chimeric mice exhibited a remarkable delay and reduction of wasting and ataxia despite their substantial amount of mutant tissue and dying cells, revealing a robust mechanism that partially compensates for massive PC death. Niemann-Pick disease type C is a deadly neurodegenerative disease that is most often due to mutations in a gene called npc1. As a consequence of intracellular lipid trafficking defects, patients with Niemann-Pick type C, and mice with the same disease, lose an important class of cerebellar neurons called Purkinje cells (PCs). Npc1 (the protein coded by npc1) might be needed in other cell types to produce substances that nourish PCs or within the PCs themselves. To see which is true, the researchers constructed genetically mosaic mice in which some cells have mutant Npc1 and some have normal Npc1 function. In the cerebella of these mosaic mice, PCs lacking Npc1 continued to die even while surrounded by normal cells, while normal PCs appeared unaffected by their partially mutant surroundings. From these findings, the researchers concluded that the neurodegeneration is due to a problem within PCs and not due to a lack of supporting factors provided by other cells or an extrinsic toxic or inflammatory insult. Npc1 probably functions within PCs to allow critical transport processes necessary for cell survival. The researchers also found that the degenerating PCs undergo a complex process called autophagy in which the cells sense a lack of key nutrients and start to break down their own structures to feed themselves. By identifying exactly which cells require Npc1 function, the researchers set the stage for investigating the exact molecular roles of Npc1 protein in the cells where it is most needed.