Jan 4, 2018

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

Qian ZhangHo Yin Edwin Chan


Polyglutamine (polyQ) diseases are a class of progressive neurodegenerative disorders characterized by the expression of both expanded CAG RNA and misfolded polyQ protein. We previously reported that the direct interaction between expanded CAG RNA and nucleolar protein nucleolin (NCL) impedes preribosomal RNA (pre-rRNA) 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 CAG RNA. When administered to a cell model, BIND potently inhibited cell death induced by expanded CAG RNA with an IC50 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 pre-45s rRNA Through isothermal titration calorimetry analysis, we demonstrated that BIND suppresses nucleolar stress via a direct interaction with CAG RNA in a length-dependent manner. The mean binding constants (KD) of BIND to SCA2 CAG22 , SCA2 CAG42 , SCA2 CAG55 , and SCA2 CAG72 RNA are 17.28, 5.60, 4.83, and...Continue Reading

  • References60
  • Citations3


  • References60
  • Citations3


Mentioned in this Paper

Establishment and Maintenance of Localization
In Vivo
Mucocutaneous Lymph Node Syndrome
Abnormal Degeneration
HEK293 Cells
General Adaptation Syndrome
Transcription, Genetic
Neurodegenerative Disorders Pathway

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Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis