Targeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology

Kyota Fujita, Xigui Chen, Hidenori Homma, Kazuhiko Tagawa, Mutsuki Amano, Ayumu Saito, Seiya Imoto, Hiroyasu Akatsu, Yoshio Hashizume, Kozo Kaibuchi, Satoru Miyano and Hitoshi Okazawa ()
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Kyota Fujita: Tokyo Medical and Dental University
Xigui Chen: Tokyo Medical and Dental University
Hidenori Homma: Tokyo Medical and Dental University
Kazuhiko Tagawa: Tokyo Medical and Dental University
Mutsuki Amano: Nagoya University
Ayumu Saito: The University of Tokyo
Seiya Imoto: The University of Tokyo
Hiroyasu Akatsu: Nagoya City University Graduate School of Medical Sciences
Yoshio Hashizume: Aichi Medical University
Kozo Kaibuchi: Nagoya University
Satoru Miyano: The University of Tokyo
Hitoshi Okazawa: Tokyo Medical and Dental University

Nature Communications, 2018, vol. 9, issue 1, 1-21

Abstract: Abstract Mutations in the progranulin (PGRN) gene cause a tau pathology-negative and TDP43 pathology-positive form of frontotemporal lobar degeneration (FTLD-TDP). We generated a knock-in mouse harboring the R504X mutation (PGRN-KI). Phosphoproteomic analysis of this model revealed activation of signaling pathways connecting PKC and MAPK to tau prior to TDP43 aggregation and cognitive impairments, and identified PKCα as the kinase responsible for the early-stage tau phosphorylation at Ser203. Disinhibition of Gas6 binding to Tyro3 due to PGRN reduction results in activation of PKCα via PLCγ, inducing tau phosphorylation at Ser203, mislocalization of tau to dendritic spines, and spine loss. Administration of a PKC inhibitor, B-Raf inhibitor, or knockdown of molecules in the Gas6-Tyro3-tau axis rescues spine loss and cognitive impairment of PGRN-KI mice. Collectively, these results suggest that targeting of early-stage and aggregation-independent tau signaling represents a promising therapeutic strategy for this disease.

Date: 2018
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DOI: 10.1038/s41467-018-02821-z

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