Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology
Koyo Tsujikawa, Kohei Hamanaka, Yuichi Riku, Yuki Hattori, Norikazu Hara, Yohei Iguchi, Shinsuke Ishigaki, Atsushi Hashizume, Satoko Miyatake, Satomi Mitsuhashi, Yu Miyazaki, Mayumi Kataoka, Jiayi Li, Keizo Yasui, Satoshi Kuru, Haruki Koike, Kenta Kobayashi, Naruhiko Sahara, Norio Ozaki, Mari Yoshida, Akiyoshi Kakita, Yuko Saito, Yasushi Iwasaki, Akinori Miyashita, Takeshi Iwatsubo, Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI), Takeshi Ikeuchi, Takaki Miyata, Gen Sobue, Naomichi Matsumoto, Kentaro Sahashi, Masahisa Katsuno
Abstract
While amyloid-β lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.