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

• DOI: 10.1016/j.nbd.2007.06.012
• Publication Date: 2007-06-26T11:18:32Z
• Authors: Laura Ahtiainen; Julia Kolikova; Aino-Liisa Mutka; Kaisu Luiro; Massimiliano Gentile; Elina Ikonen; Leonard Khiroug; Anu Jalanko; Outi Kopra
• Keywords: Homeostasis; Neuronal ceroid lipofuscinosis; Calcium imaging

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.