Exp Mol Med.  2017 May;49(5):e333. 10.1038/emm.2017.56.

Transcriptome analyses of chronic traumatic encephalopathy show alterations in protein phosphatase expression associated with tauopathy

Affiliations
  • 1Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Korea. jeongsun@snu.ac.kr hoonryu@bu.edu
  • 2Department of Biochemistry and Molecular Biology, College of Medicine, Seoul National University, Seoul, Korea.
  • 3Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
  • 4Macrogen Inc., Seoul, Korea.
  • 5Center for Neuromedicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea. jeongsun@snu.ac.kr hoonryu@bu.edu
  • 6Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.
  • 7Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea.
  • 8Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea.
  • 9Department of Neuroscience, University of Science and Technology, Daejeon, Korea.
  • 10Department of Neurosurgery, Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Korea.
  • 11Center for the Study of Traumatic Encephalopathy, Boston University School of Medicine, Boston, MA, USA. jeongsun@snu.ac.kr hoonryu@bu.edu
  • 12VA Boston Healthcare System, Boston, MA, USA.
  • 13Alzheimer's Disease Center and Department of Neurology, Boston University, School of Medicine, Boston, MA, USA.

Abstract

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder that is associated with repetitive head injury and has distinctive neuropathological features that differentiate this disease from other neurodegenerative diseases. Intraneuronal tau aggregates, although they occur in different patterns, are diagnostic neuropathological features of CTE, but the precise mechanism of tauopathy is not known in CTE. We performed whole RNA sequencing analysis of post-mortem brain tissue from patients with CTE and compared the results to normal controls to determine the transcriptome signature changes associated with CTE. The results showed that the genes related to the MAP kinase and calcium-signaling pathways were significantly downregulated in CTE. The altered expression of protein phosphatases (PPs) in these networks further suggested that the tauopathy observed in CTE involves common pathological mechanisms similar to Alzheimer's disease (AD). Using cell lines and animal models, we also showed that reduced PPP3CA/PP2B phosphatase activity is directly associated with increases in phosphorylated (p)-tau proteins. These findings provide important insights into PP-dependent neurodegeneration and may lead to novel therapeutic approaches to reduce the tauopathy associated with CTE.

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