title: 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.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, United States.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Schultz
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, United States.
authors.forename: Kelsey L
authors.initials: KL
authors.lastname: Krus
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, United States. Electronic address: liebermn@umich.edu.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
mesh_terms: D000818:Animals; D001343:Autophagy; D002352:Carrier Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein
keywords: Autophagy; ER-phagy; Endoplasmic reticulum; Lysosomal storage disorder; Lysosome; Niemann-Pick type C disease