U1 small nuclear RNA overexpression implicates autophagic-lysosomal system associated with AD

Abstract

Recently, we reported that presenilin 1 considerably increased the expression level of U1 small nuclear RNA (snRNA) accompanied with the adverse change of amyloid precursor protein (APP) expression, β-amyloid (Aβ) production and cell apoptosis. In the present study, it was found that U1 snRNA overexpression significantly elevated the expression level of autophagy. Moreover, rapamycin further enhanced the Aβ production and cell apoptosis, whereas these processes were effectively inhibited by 3-MA. Acridine orange staining images showed that U1 snRNA overexpression not only activated autophagy pathway, but also led to the autophagic-lysosomal system dysfunction in cells. Immunofluorescence assay showed autophagic vacuoles localization with APP, which was the precursor protein of main component of toxic protein in AD. Meanwhile, the superoxide dismutase activity was remarkably decreased and MDA level was significantly increased by U1 snRNA overexpression in cells, suggesting that there was a possible pathway to elucidate how the U1 snRNA overexpression induced cell damage. We further found that U1 snRNA overexpression altered lysosomal biogenesis and autophagic-lysosomal fusion. In combination with our previous results, it suggests that the malfunction of autophagy pathway provides important insight into molecular mechanisms of augment the aggregation of Aβ and induction of cell apoptosis contributed to AD.

Keywords: Autophagy; Aβ; Cell damage; Lysosomal; ROS; U1 snRNA.