Ahtiainen Laura, Kolikova Julia, Mutka Aino-Liisa, Luiro Kaisu, Gentile Massimiliano, Ikonen Elina, Khiroug Leonard, Jalanko Anu, Kopra Outi
National Public Health Institute, Department of Molecular Medicine, Biomedicum Helsinki, PO Box 104, 00251 Helsinki, Finland.
Neurobiol Dis. 2007 Oct;28(1):52-64. doi: 10.1016/j.nbd.2007.06.012. Epub 2007 Jun 23.
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.
婴儿神经元蜡样脂褐质沉积症（INCL）是一种严重的儿童神经退行性疾病，其特征是新皮质神经元选择性死亡。为了解INCL的早期疾病机制，我们研究了培养的Ppt1(Deltaex4)基因敲除小鼠神经元和急性脑片。整体转录谱分析显示，基因敲除小鼠的关键神经元功能失调，包括胆固醇代谢、神经元成熟和钙稳态。胆固醇代谢发生了重大变化；甾醇生物合成增强，细胞水平上甾醇的稳态量发生改变。Ppt1(Deltaex4)神经元的早期成熟也有变化，表现为神经干细胞增殖能力增强。基因敲除神经元的电生理特性未改变，表明幼龄动物的突触功能未受损。然而，基因敲除神经元从谷氨酸诱导的钙瞬变中恢复的效率更高，这可能表明存在神经保护激活作用。这项研究证实，INCL中的神经元失调与神经元成熟、脂质代谢和钙稳态有关。
