Tau binding protein CAPON induces tau aggregation and neurodegeneration

• Published in: Nature communications Vol. 10; no. 1; p. 2394
• Main Authors: Hashimoto, Shoko, Matsuba, Yukio, Kamano, Naoko, Mihira, Naomi, Sahara, Naruhiko, Takano, Jiro, Muramatsu, Shin-ichi, Saido, Takaomi C., Saito, Takashi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.06.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/2; 13/51; 13/95; 38/39; 59/57; 631/378/1689/1283; 631/378/1934; 64/110; 96/35; 96/44; Accumulation; Adaptor Proteins, Signal Transducing - metabolism; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloidosis; Animals; Atrophy; Brain; Caspase 3 - metabolism; Cell Death; Chromatography, Liquid; Disease Models, Animal; Gene Knock-In Techniques; Glutamic acid receptors; Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Humanities and Social Sciences; Humans; Immunoprecipitation; Mass Spectrometry; Mice; multidisciplinary; N-Methyl-D-aspartic acid receptors; Neurodegeneration; Neurodegenerative diseases; Neurons - metabolism; Neurons - pathology; Nitric oxide; Nitric-oxide synthase; Oligomerization; Pathogenesis; Phenotypes; Protein Aggregation, Pathological - metabolism; Protein Aggregation, Pathological - pathology; Proteins; Pyramidal Cells - metabolism; Pyramidal Cells - pathology; Science; Science (multidisciplinary); Tau protein; tau Proteins - metabolism; Tauopathies
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10278-x

To understand the molecular processes that link Aβ amyloidosis, tauopathy and neurodegeneration, we screened for tau-interacting proteins by immunoprecipitation/LC-MS. We identified the carboxy-terminal PDZ ligand of nNOS (CAPON) as a novel tau-binding protein. CAPON is an adaptor protein of neuronal nitric oxide synthase (nNOS), and activated by the N-methyl-D-aspartate receptor. We observed accumulation of CAPON in the hippocampal pyramidal cell layer in the App NL-G-F -knock-in (KI) brain. To investigate the effect of CAPON accumulation on Alzheimer’s disease (AD) pathogenesis, CAPON was overexpressed in the brain of App NL-G-F mice crossbred with MAPT (human tau)-KI mice. This produced significant hippocampal atrophy and caspase3-dependent neuronal cell death in the CAPON-expressing hippocampus, suggesting that CAPON accumulation increases neurodegeneration. CAPON expression also induced significantly higher levels of phosphorylated, oligomerized and insoluble tau. In contrast, CAPON deficiency ameliorated the AD-related pathological phenotypes in tauopathy model. These findings suggest that CAPON could be a druggable AD target. To understand the molecular processes that link Aβ amyloidosis, tauopathy and neurodegeneration, the authors screened for tau-interacting proteins. They demonstrated that a novel tau binding protein CAPON accelerates tau pathology and neuronal cell death in an Alzheimer’s disease mouse model.