Cholesterol and neurodegeneration

Abstract

AbstractPurpose Based on our previous studies (Mauch et al., 2001 Science; Nieweg et al., 2009 J Neurochem), we hypothesized that retinal ganglion cells (RGCs) depend on the endocytotic import of glia‐derived cholesterol and that a breakdown of this import causes neurodegeneration (Pfrieger, 2003). The membrane protein Niemann‐Pick C1 mediates the exit of externally acquired cholesterol from the endosomal‐lysosomal system. Therefore, we studied, whether mice lacking Niemann‐Pick typ C protein1 (NPC1) due to a spontaneous mutation, show pathologic changes in RGCs and elsewhere in the retina. These mice are a model for the lysosomal storage disorder Niemann‐Pick type C.Methods We analysed the retinal phenotype of NPC1‐deficient mice by electroretinography, scanning laser ophthalmoscopy and histologic analysis.Results We observed striking signs of degeneration in retinae from two‐months‐old NPC1‐deficient mice. This included impaired visual function, accumulation of lipofuscin in the retinal pigment epithelium (RPE) layer, degeneration of photoreceptor outer segments, disruption of synaptic layers and upregulation of proteins that mediate cellular cholesterol release under the transcriptional control of the liver X receptor (Claudepierre et al., 2010 MCN). Notably, we observed an increase in LC3, an autophagy marker, specifically in the ganglion cell layer and in the RPE.Conclusion Our results support the idea that cells in the retina depend on the intercellular exchange of cholesterol via lipoprotein‐mediated transport. Moreover, our results suggest that disturbance of lipid metabolism in the retina contributes to neurodegeneration.