Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol metabolism and calcium homeostasis prior to synaptic dysfunction

Neurobiology of Disease

Anu Jalanko¹  Outi Kopra¹  Laura Ahtiainen¹  Kaisu Luiro¹  Massimiliano Gentile¹  Aino-Liisa Mutka²  Elina Ikonen²  Julia Kolikova³  Leonard Khiroug³ 

[1] National Public Health Institute, Department of Molecular Medicine, Biomedicum Helsinki, PO Box 104, 00251 Helsinki, Finland;University of Helsinki, Institute of Biomedicine/Anatomy, PO Box 63, 00014 University of Helsinki, Finland;University of Helsinki, Neuroscience Center, PO Box 56, 00014 University of Helsinki, Finland;

关键词: Palmitoyl protein thioesterase 1;    Infantile neuronal ceroid lipofuscinosis;    Neuron culture;    Synapse;    Neuron maturation;    Calcium homeostasis;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 Ppt1Deltaex4 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 Ppt1Deltaex4 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.

【 授权许可】

Unknown