Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol and calcium homeostasis prior to synaptic dysfunction
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Neurobiol Dis. 2007 Oct;28(1):52-64. Epub 2007 Jun 23
Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol metabolism and calcium homeostasis prior to synaptic dysfunction
Ahtiainen L, Kolikova J, Mutka AL, Luiro K, Gentile M, Ikonen E, Khiroug L, Jalanko A, Kopra O.
National Public Health Institute, Department of Molecular Medicine, Biomedicum Helsinki, PO Box 104, 00251 Helsinki, Finland.
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.
PubMed ID and Record
Neurobiol Dis. 2007 Oct;28(1):52-64. Epub 2007 Jun 23
Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol metabolism and calcium homeostasis prior to synaptic dysfunction
Ahtiainen L, Kolikova J, Mutka AL, Luiro K, Gentile M, Ikonen E, Khiroug L, Jalanko A, Kopra O.
National Public Health Institute, Department of Molecular Medicine, Biomedicum Helsinki, PO Box 104, 00251 Helsinki, Finland.
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.
PubMed ID and Record
posted by Dr.Koudinov @ 8:41 PM
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