title: The natural history of cerebellar degeneration of Niemann-Pick C mice monitored in vitro.
abstract: OBJECTIVE
  Niemann-Pick type C (NPC) disease is a fatal hereditary lysosomal lipid storage disease caused by mutations in NPC1 or NPC2. It is still unknown how this disorder evokes clinical signs. Typically, patients develop severe cerebellar ataxia due to progressive Purkinje cell loss. Hitherto, in vitro studies did not allow monitoring the natural process of NPC-associated Purkinje cell degeneration. Aim of this study was to evaluate whether organotypic slice cultures are usable to monitor the natural process of NPC-associated Purkinje-cell degeneration.
  
  
  METHODS
  We used organotypic cerebellar slice cultures of a well-established NPC mouse model to display the natural history of cerebellar degeneration in vitro and cultivated them for a prolonged time period of 6 weeks for the first time. Moreover we tested several therapeutic candidates and evaluated their effect on Purkinje-cell survival.
  
  
  RESULTS
  Our approach proves that it is possible to monitor and to prevent NPC-related Purkinje cell death reliably in vitro. This is beneficial because in vivo Purkinje cell loss directly translates into clinical signs. Thus, therapeutically interesting compounds can be tested in vitro, not only to correct biochemical abnormalities, but also to show the likelihood of a compound to prevent ataxia. As to be expected from the results of previous animal experiments, 2-hydroxypropyl-β-cyclodextrin rescued Purkinje cells. We also discovered that 3-methyladenine preserved Purkinje cell numbers by adjusting the autophagic flux in NPC slices.
  
  
  CONCLUSIONS
  We provide evidence that cerebellar slice cultures are a powerful in vitro tool to study NPC-associated Purkinje cell death in an organotypic setting.
authors.affiliation: Institute for Integrative Neuroanatomy, Charité, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Marschalek
authors.forename: Frank
authors.initials: F
authors.lastname: Albert
authors.forename: Volker
authors.initials: V
authors.lastname: Meske
authors.forename: Thomas Georg
authors.initials: TG
authors.lastname: Ohm
mesh_terms: D000818:Animals; D002470:Cell Survival; D002526:Cerebellar Diseases / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D051379:Mice; D008807:Mice, Inbred BALB C; D008818:Mice, Neurologic Mutants; D052556:Niemann-Pick Disease, Type C / Q000150:complications* / Q000188:drug therapy / Q000473:pathology*; D011689:Purkinje Cells / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D046509:Tissue Culture Techniques
keywords: 2-hydroxypropyl-β-cyclodextrin; 3-methyladenine; Niemann-Pick disease type C; neurodegeneration; organotypic slice cultures