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

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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.