Rolle des Endoplasmatischen Retikulums und exzitotoxischer Kalziumdysregulation bei Motoneurondegeneration zur Klärung der Pathogenese der Amyotrophen Lateralsklerose

致命的神经退行性疾病肌萎缩侧索硬化症（ALS）主要影响运动系统，并且在1-2%的病例中由Cu/Zn超氧化物歧化酶基因（SOD 1）突变引起。选择性脆弱的运动神经元退化与线粒体功能障碍和蛋白质加工紊乱的迹象，这可能是慢性兴奋毒性的结果。该项目旨在确定AMPA受体激活，钙诱导的钙释放，线粒体功能和内质网（ER）中蛋白质加工的分子机制。申请人的由AMPA受体激活驱动的ER和线粒体之间的循环钙信号传导模型产生了基本假设。在杂交NSC 34细胞中，运动神经元培养物和斑马鱼运动神经元荧光钙探针靶向线粒体和ER报告AMPA受体激活期间的钙动力学。标记的荧光蛋白指示在天然和兴奋性毒性条件下通过改变AMPA受体的动力学而产生的ER中的蛋白质折叠。将研究突变的人SOD 1对线粒体功能和ER蛋白加工的影响。将确定未来药物治疗的靶点。

The fatal neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS) primarily affects the motor system and is caused by mutations of the Cu/Zn superoxidedismutase gene (SOD1) in 1-2% of cases. Selectively vulnerable motoneurons degenerate with signs of mitochondrial dysfunction and disturbed protein processing which may be the result of chronic excitoxicity. The project aims to identify the molecular mechanisms linking AMPA receptor activation, calcium-induced calcium release, mitochondrial function and protein processing in the endoplasmic reticulum (ER). The applicant¿s model of cyclic calcium signalling between the ER and mitochondria driven by AMPA receptor activation generates basic hypotheses. In hybrid NSC34 cells, motoneuron cultures and Zebra fish motoneurons fluorescent calcium probes targeted to mitochondria and ER report the calcium dynamics during AMPA receptor activation. Tagged fluorescent proteins indicate protein folding in the ER in native and excitotoxic conditions created by altering the kinetics of AMPA receptors. The impact of mutant human SOD1 on mitochondrial function and ER protein processing will be studied. Targets of future drug therapy will be identified.