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

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.

• Authors: Jeong-Sun Seo, Seungbok Lee, Jong-Yeon Shin, Yu Jin Hwang, Hyesun Cho, Seong-Keun Yoo, Yunha Kim, Sungsu Lim, Yun Kyung Kim, Eun Mi Hwang, Su Hyun Kim, Chong-Hyun Kim, Seung Jae Hyeon, Ji-Young Yun, Jihye Kim, Yona Kim, Victor E Alvarez, Thor D Stein, Junghee Lee, Dong Jin Kim, Jong-Il Kim, Neil W Kowall, Hoon Ryu, Ann C McKee
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 49 Issue 5 Pg. e333 (05 19 2017) ISSN: 2092-6413 [Electronic] United States
• PMID: 28524178 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• tau Proteins
• Calcineurin
• PPP3CA protein, human

Topics

• Aged
• Aged, 80 and over
• Animals
• Calcineurin (genetics, metabolism)
• Calcium Signaling
• Chronic Traumatic Encephalopathy (genetics, metabolism, pathology)
• Down-Regulation
• Female
• HEK293 Cells
• Humans
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Phosphorylation
• Protein Processing, Post-Translational
• Transcriptome
• tau Proteins (metabolism)