Ndufs4 ablation shows an elevated GFAP and a decreased synaptophysin expression in mouse hippocampus.

概要

Respiratory chain complex I dysfunction in brain cells is involved in many neurodegenerative diseases. NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and its mutation is associated with Leigh syndrome in human. Ndufs4-KO mice are also recognized as the model mice of Leigh syndrome and show impairment in several physiological phenotypes such as growth and motor functions. However, the molecular biological role of Ndufs4 in neuronal function is poorly understood. In this study, upon Ndufs4 expression confirmation in NeuN-positive neurons and GFAP-positive astrocytes of mouse hippocampus, I found significant decrease of mitochondrial respiration in Ndufs4-KO mouse hippocampus. Furthermore, GFAP expression was elevated in in vivo hippocampus of Ndufs4-KO mouse, but not changed in in vitro primary cultured astrocytes. Although there was no change in the number of NeuN expressing neurons in Ndufs4-KO hippocampus, the expression of synaptophysin, a presynaptic protein, was decreased. To investigate the detailed mechanism, I silenced Ndufs4 expression followed by induction of differentiation in Neuro2A cells and found shorter neurite lengths with decreased expression of synaptophysin per length as well as decrease in activity of ERK signalling. These results suggest that Ndufs4 may regulate synaptophysin expression in hippocampus and thus altered synaptoplasticity may lead to astrogliosis which is characterized by increased GFAP expression. This knowledge may provide novel insights in hippocampal pathophysiology of neurodegenerative disease for designing the effective treatment strategy.