title: Pathological cholesterol metabolism fails to modify electrophysiological properties of afflicted neurones in Niemann-Pick disease type C.
abstract: Niemann-Pick disease type C (NPC) is a recessive inherited neurovisceral lipid storage disease characterized by progressive motor impairment and a loss of neurones including those integrated into the motor system. One of the key neuropathological findings is the intracellular accumulation of lysosomes enriched with free cholesterol. This accumulation is due to impaired transport proteins named NPC1 (approx. 95% of the cases) or NPC2 (approx. 5%) responsible for the transport of endocytosed cholesterol from lysomes to plasma membranes. The perturbed lipid-transport in NPC cells leads to an altered lipid composition of the plasma membrane. Available evidence suggests that the lipid matrix influences the electrophysical properties of ion channels in membranes. We therefore evaluated whether electrophysiological properties of NPC neurones differ from healthy neurones. Both, acute brain slices and primary neuronal cell cultures from wildtype and NPC mice, a well-established mouse model for the Niemann-Pick type C disease, were used for a comparison of electrophysiological properties like resting membrane potential, input resistance, action potential amplitudes and synaptic properties of the neurones. In addition we optically recorded the changes of intraneuronal calcium levels elicited by depolarization. Our results show that the characteristics of ion channels in NPC neurones do not differ significantly from wildtype neurones. We therefore conclude that gross alterations of the electrophysiological properties of neurones will probably not initiate or substantially contribute to the development of the motor impairment or other neurological signs of NPC.
authors.affiliation: Center of Anatomy, Charité, Institute of Integrative Neuroanatomy, Department of Clinical Cell and Neurobiology, Schumann Strasse 20-21, 10098 Berlin, Germany.
authors.forename: R A
authors.initials: RA
authors.lastname: Deisz
authors.forename: V
authors.initials: V
authors.lastname: Meske
authors.forename: S
authors.initials: S
authors.lastname: Treiber-Held
authors.forename: F
authors.initials: F
authors.lastname: Albert
authors.forename: T G
authors.initials: TG
authors.lastname: Ohm
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020013:Calcium Signaling / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005372:Filipin; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008818:Mice, Neurologic Mutants; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D011506:Proteins / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics; D033921:Vesicular Transport Proteins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; C497045:Npc2 protein, mouse; D011506:Proteins; D033921:Vesicular Transport Proteins; D005372:Filipin; D002784:Cholesterol