title: Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol metabolism and calcium homeostasis prior to synaptic dysfunction.
abstract: Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disorder of children, characterized by selective death of neocortical neurons. To understand early disease mechanisms in INCL, we have studied Ppt1(Deltaex4) knock-out mouse neurons in culture and acute brain slices. Global transcript profiling showed deregulation of key neuronal functions in knock-out mice including cholesterol metabolism, neuronal maturation, and calcium homeostasis. Cholesterol metabolism showed major changes; sterol biosynthesis was enhanced and steady-state amounts of sterols were altered at the cellular level. Changes were also present in early maturation of Ppt1(Deltaex4) neurons indicated by increased proliferative capacity of neuronal stem cells. Knock-out neurons presented unaltered electrophysiological properties suggesting uncompromised synaptic function in young animals. However, knock-out neurons exhibited more efficient recovery from glutamate-induced calcium transients, possibly indicating neuroprotective activation. This study established that the neuronal deregulation in INCL is linked to neuronal maturation, lipid metabolism and calcium homeostasis.
authors.affiliation: National Public Health Institute, Department of Molecular Medicine, Biomedicum Helsinki, PO Box 104, 00251 Helsinki, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Ahtiainen
authors.forename: Julia
authors.initials: J
authors.lastname: Kolikova
authors.forename: Aino-Liisa
authors.initials: AL
authors.lastname: Mutka
authors.forename: Kaisu
authors.initials: K
authors.lastname: Luiro
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Gentile
authors.forename: Elina
authors.initials: E
authors.lastname: Ikonen
authors.forename: Leonard
authors.initials: L
authors.lastname: Khiroug
authors.forename: Anu
authors.initials: A
authors.lastname: Jalanko
authors.forename: Outi
authors.initials: O
authors.lastname: Kopra
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000378:metabolism; D006706:Homeostasis; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D013234:Stem Cells / Q000166:cytology; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D013869:Thiolester Hydrolases / Q000172:deficiency* / Q000235:genetics
chemical_list: D002784:Cholesterol; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D002118:Calcium