A peptidylic inhibitor for neutralizing expanded RNA-induced nucleolar stress in polyglutamine diseases.

Polyglutamine (polyQ) diseases are a class of progressive neurodegenerative disorders characterized by the expression of both expanded RNA and misfolded polyQ protein. We previously reported that the direct interaction between expanded RNA and nucleolar protein nucleolin (NCL) impedes RNA () transcription, and eventually triggers nucleolar stress-induced apoptosis in polyQ diseases. Here, we report that a 21-amino acid peptide, named "beta-structured inhibitor for neurodegenerative diseases" (BIND), effectively suppresses toxicity induced by expanded RNA. When administered to a cell model, BIND potently inhibited cell death induced by expanded RNA with an IC value of ∼0.7 µM. We showed that the function of BIND is dependent on Glu2, Lys13, Gly14, Ile18, Glu19, and Phe20. BIND treatment restored the subcellular localization of nucleolar marker protein and the expression level of Through isothermal titration calorimetry analysis, we demonstrated that BIND suppresses nucleolar stress via a direct interaction with RNA in a length-dependent manner. The mean binding constants () of BIND to , , , and RNA are 17.28, 5.60, 4.83, and 0.66 µM, respectively. In vivo, BIND ameliorates retinal degeneration and climbing defects, and extends the lifespan of expressing expanded RNA. These effects suggested that BIND can suppress neurodegeneration in diverse polyQ disease models in vivo and in vitro without exerting observable cytotoxic effect. Our results collectively demonstrated that BIND is an effective inhibitor of expanded RNA-induced toxicity in polyQ diseases.