title: Deficient mitochondrial Ca(2+) buffering in the Cln8(mnd) mouse model of neuronal ceroid lipofuscinosis.
abstract: Neuronal ceroid lipofuscinoses (NCLs) are a group of genetic childhood-onset progressive brain diseases characterized by a decline in mental and motor capacities, epilepsy, visual loss and premature death. Using patch clamp, fluorescence imaging and caged Ca(2+) photolysis, we evaluated the mechanisms of neuronal Ca(2+) clearance in Cln8(mnd) mice, a model of the human NCL caused by mutations in the CLN8 gene. In Cln8(mnd) hippocampal slices, Ca(2+) clearance efficiency in interneurons and, to some extent, principal neurons declined with age. In cultured Cln8(mnd) hippocampal neurons, clearance of large Ca(2+) loads was inefficient due to impaired mitochondrial Ca(2+) uptake. In contrast, neither Ca(2+) uptake by sarco/endoplasmic reticulum Ca(2+) ATPase, nor Ca(2+) extrusion through plasma membrane was affected by the Cln8 mutation. Excitotoxic glutamate challenge caused Ca(2+) deregulation more readily in Cln8(mnd) than in wt neurons. We propose that neurodegeneration in human CLN8 disorders is primarily caused by reduced mitochondrial Ca(2+) buffering capacity.
authors.affiliation: Neuroscience Center, University of Helsinki, Finland.
authors.forename: Julia
authors.initials: J
authors.lastname: Kolikova
authors.forename: Ramil
authors.initials: R
authors.lastname: Afzalov
authors.forename: Alexander
authors.initials: A
authors.lastname: Surin
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.forename: Leonard
authors.initials: L
authors.lastname: Khiroug
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D016257:Fura-2; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis; D007395:Interneurons / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: C498493:Cln8 protein, mouse; D008565:Membrane Proteins; D018698:Glutamic Acid; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium; D016257:Fura-2