The tyrosine phosphatase PTPN13/FAP-1 links calpain-2, TBI and tau tyrosine phosphorylation

• Published in: Scientific reports 2017-09, Vol.7 (1), p.11771-13, Article 11771
• Main Authors: Wang, Yubin, Hall, Randy A., Lee, Moses, Kamgar-parsi, Andysheh, Bi, Xiaoning, Baudry, Michel
• Format: Article
• Language: English
• Subjects: 13/1; 14; 14/19; 631/378/1689; 631/378/1689/1283; 631/378/87; 96; 96/95; Alzheimer's disease; Calpain; Humanities and Social Sciences; Isoforms; Kinases; multidisciplinary; Neurodegenerative diseases; Phosphatase; Phosphorylation; Protein-tyrosine-phosphatase; Science; Science (multidisciplinary); Synaptic plasticity; Tau protein; Traumatic brain injury
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-12236-3

Traumatic brain injury (TBI) increases the risk of Alzheimer’s disease (AD). Calpain activation and tau hyperphosphorylation have been implicated in both TBI and AD. However, the link between calpain and tau phosphorylation has not been fully identified. We recently discovered that the two major calpain isoforms in the brain, calpain-1 and calpain-2, play opposite functions in synaptic plasticity and neuronal survival/death, which may be related to their different C-terminal PDZ binding motifs. Here, we identify the tyrosine phosphatase PTPN13 as a key PDZ binding partner of calpain-2. PTPN13 is cleaved by calpain-2, which inactivates its phosphatase activity and generates stable breakdown products (P13BPs). We also found that PTPN13 dephosphorylates and inhibits c-Abl. Following TBI, calpain-2 activation cleaved PTPN13, activated c-Abl and triggered tau tyrosine phosphorylation. The activation of this pathway was responsible for the accumulation of tau oligomers after TBI, as post-TBI injection of a calpain-2 selective inhibitor inhibited c-Abl activation and tau oligomer accumulation. Thus, the calpain-2-PTPN13-c-Abl pathway provides a direct link between calpain-2 activation and abnormal tau aggregation, which may promote tangle formation and accelerate the development of AD pathology after repeated concussions or TBI. This study suggests that P13BPs could be potential biomarkers to diagnose mTBI or AD.