title: The autophagic defect in Niemann-Pick disease type C neurons differs from somatic cells and reduces neuronal viability.
abstract: Niemann-Pick disease type C (NPC) is a fatal, progressive neurovisceral disorder. Several studies report that the autophagic flux is disturbed in NPC1-deficient (NPC1-/-) cells. Since it has been suggested that the autophagic defect may contribute to the neurodegeneration, we used cell cultures of NPC1-deficient and NPC1-wildtype neurons to investigate whether the disturbance influences neuronal survival. We found a genotype-dependent difference in survival, when autophagy is induced during culturing. NPC1-deficient neurons are more sensitive to rapamycin treatment and starvation than wildtype neurons. The subsequent search for defects in regulatory components of the autophagic pathway and the autophagic flux brought up results which differ from previous reports on somatic cells in one essential aspect: we exclude that an enhanced formation of autophagosomes contributes to the imbalanced autophagic flux in NPC1 deficient neurons. We found that solely the clearance of autophagosomes is delayed in these cells, which leads to an accumulation of autophagic vacuoles within the lysosomal compartment. Lowering the abnormal lipid load of the acidic organelles with cyclodextrin is sufficient to correct the autophagic flux and prevents premature death of NPC1-/- neurons under autophagic stress. From our results, we conclude that a pharmacological intervention in the neuropathology of NPC-disease should focus on the restoration of the lysosomal degradation capacity of cells.
authors.affiliation: Center of Anatomy, Institute of Integrative Neuroanatomy, Department of Clinical Cell and Neurobiology, Charité, Charité-Platz 1, 10098 Berlin, Germany. Electronic address: volker.meske@charite.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Meske
authors.affiliation: Center of Anatomy, Institute of Integrative Neuroanatomy, Department of Clinical Cell and Neurobiology, Charité, Charité-Platz 1, 10098 Berlin, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Erz
authors.affiliation: Center of Anatomy, Institute of Integrative Neuroanatomy, Department of Clinical Cell and Neurobiology, Charité, Charité-Platz 1, 10098 Berlin, Germany.
authors.forename: Timm
authors.initials: T
authors.lastname: Priesnitz
authors.affiliation: Center of Anatomy, Institute of Integrative Neuroanatomy, Department of Clinical Cell and Neurobiology, Charité, Charité-Platz 1, 10098 Berlin, Germany.
authors.forename: Thomas-Georg
authors.initials: TG
authors.lastname: Ohm
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071189:Autophagy-Related Protein-1 Homolog; D000071186:Beclin-1; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000503:physiopathology*; D015388:Organelles / Q000502:physiology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014617:Vacuoles / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse; D002784:Cholesterol; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C112444:Ulk1 protein, mouse; D054648:Protein Phosphatase 2
keywords: Acidic compartment; Autophagy; Cholesterol; Neurons; Niemann–Pick type C