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

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder associated with repetitive head injury (RHI) with distinctive neuropathological features that differentiate it from other neurodegenerative diseases. Intraneuronal tau aggregates, albeit in different patterns, are diagnostic neuropathological features of CTE but the exact mechanism of tauopathy is not known in CTE. We performed whole RNA sequencing analysis of postmortem brain tissue from patients with CTE and compared the results to normal controls to determine the transcriptome signature changes associated with CTE. We found that genes related to MAP Kinase and calcium signaling pathways were significantly down regulated in CTE. Altered expression of protein phosphatases (PP) in these networks further suggest that the tauopathy found in CTE shares common pathological mechanisms as similar to Alzheimer’s disease (AD). Using cell lines and animal models we also showed that reduced PPP3CA/PP2B phosphatase activity is directly linked to increases in phosphorylated (p)-tau proteins. These findings provide important insights into PP-dependent neurodegeneration that may lead to novel therapeutic approaches to reduce the tauopathy associated with CTE.