Lysosome and endoplasmic reticulum quality control pathways in Niemann-Pick type C disease

Abstract

Lysosomal storage diseases result from inherited deficiencies of lysosomal hydrolytic activities or lipid transport. Collectively, these disorders are a common cause of morbidity in the pediatric population and are often associated with severe neurodegeneration. Among this group of diseases is Niemann-Pick type C, an autosomal recessive disorder of lipid trafficking that causes cognitive impairment, ataxia and death, most often in childhood. Here, we review the current knowledge of disease pathogenesis, with particular focus on insights gleaned from genetics and the study of model systems. Critical advances in understanding mechanisms that regulate intracellular cholesterol trafficking have emerged from this work and are highlighted. We review effects of disease-causing mutations on quality control pathways involving the lysosome and endoplasmic reticulum, and discuss how they function to clear the most common mutant protein found in Niemann-Pick type C patients, NPC1-I1061T. Finally, we summarize insights into the mechanisms that degrade misfolded transmembrane proteins in the endoplasmic reticulum and how manipulating these quality control pathways may lead to the identification of novel targets for disease-modifying therapies. This article is part of a Special Issue entitled SI:Autophagy.

Keywords: Autophagy; ER-phagy; Endoplasmic reticulum; Lysosomal storage disorder; Lysosome; Niemann-Pick type C disease.

Figure 1. Pathways regulating NPC1-I1061T degradation

NPC1 is a multipass transmembrane glycoprotein whose folding is facilitated by the calnexin/calreticulin machinery. Folding is also promoted by binding cholesterol or oxysterols at sites in the NTD and perhaps in more C-terminal regions, such as the sterol sensing domain (highlighted by grey oval). The natively folded protein traffics through the Golgi to late endosome/lysosomes, where it facilitates efflux of unesterified cholesterol. Both WT and NPC1-I1061T, a missense mutant that causes disease, are degraded by the proteasome if they fail to properly fold. While components of the ERAD pathway that participate in this process have not been defined, cytosolic machinery including Hsp70 and CHIP have been implicated in the clearance process. Ubiquitination of NPC1 occurs on three lysine resides (318, 792 and 1180) which face the cytosol. Also implicated in the clearance of misfolded multipass transmembrane proteins is ER-phagy. Through this pathway, membrane proteins in the ER are engulfed by pre-autophagosome structures (PAS), which subsequently form autophagosomes, fuse with lysosomes, and lead to substrate degradation in autolysosomes. The extent to which this pathway contributes to NPC1 degradation is currently unknown.