Complex Effect of RNA Spliceosome Inhibition on Amyloid Precursor Protein Expression.

Complex Effect of RNA Spliceosome Inhibition on Amyloid Precursor Protein Expression. Neurochem Res. 2016 Jul 1; Authors: Zhang N, He L, Feng H, Kong Y, Wang J, Zhang J Abstract Alzheimer's disease (AD) is a worldwide health problem that requires more effective cures and better understanding. Evidence of both pathology and genetics strongly points to the amyloid precursor protein (APP) in the pathogenesis of this devastating disease. Recent studies demonstrated U1 spliceosomal proteopathy and RNA splicing deficiency in AD brains; and inhibition of certain U1 components (U1-70K and snRNA) increased APP protein level as well as its amyloidogenic cleavage products. This intriguing discovery provides a potential mechanism for amyloid formation in AD brains. To determine whether this APP-increasing effect is a general consequence of RNA splicing dysfunction, we inhibited multiple spliceosomal components individually by siRNA knockdown or chemical inhibition and examined APP protein expression in cultured cells. U1C knockdown induced similar APP increase to that by U1-70K knockdown, while U1A knockdown showed no such effect. Among the chemical treatments, isoginkgetin which blocks the assembly of U4/U5/U6 spliceosomes substantially increased APP, but spliceostatin A, sudemycin and herboxidiene which are U2 spliceosome inhibitors all decreased APP level instead. These results demonstrate the complex effect of RNA splicing inhibition on AP...
Source: Neurochemical Research - Category: Neuroscience Authors: Tags: Neurochem Res Source Type: research