The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of poly-PR/GR dipeptide repeats, which are encoded by the chromosome 9 open reading frame 72 (C9orf72) gene. Recently, it was shown that poly-PR/GR alters chromatin accessibility, which results in the stabilization and enhancement of transcriptional activity of the tumor suppressor p53 in several neurodegenerative disease models. A reduction in p53 protein levels protects against poly-PR and partially against poly-GR neurotoxicity in cells. Moreover, in model organisms, a reduction of p53 protein levels protects against neurotoxicity of poly-PR. Here, we aimed to study the detailed molecular me... More
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of poly-PR/GR dipeptide repeats, which are encoded by the chromosome 9 open reading frame 72 (C9orf72) gene. Recently, it was shown that poly-PR/GR alters chromatin accessibility, which results in the stabilization and enhancement of transcriptional activity of the tumor suppressor p53 in several neurodegenerative disease models. A reduction in p53 protein levels protects against poly-PR and partially against poly-GR neurotoxicity in cells. Moreover, in model organisms, a reduction of p53 protein levels protects against neurotoxicity of poly-PR. Here, we aimed to study the detailed molecular mechanisms of how p53 contributes to poly-PR/GR-mediated neurodegeneration. Using a combination of biophysical techniques such as nuclear magnetic resonance (NMR) spectroscopy, fluorescence polarization, turbidity assays, and differential interference contrast (DIC) microscopy, we found that p53 physically interacts with poly-PR/GR and triggers liquid-liquid phase separation of p53. We identified the p53 transactivation domain 2 (TAD2) as the main binding site for PR25/GR25 and showed that binding of poly-PR/GR to p53 is mediated by a network of electrostatic and/or hydrophobic interactions. Our findings might help to understand the mechanistic role of p53 in poly-PR/GR-associated neurodegeneration.
