TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2
Naohiro Egawa, Yuishin Izumi, Hidefumi Suzuki, Itaru Tsuge, Koji Fujita, Hitoshi Shimano, Keiichi Izumikawa, Nobuhiro Takahashi, Kayoko Tsukita, Takako Enami, Masahiro Nakamura, Akira Watanabe, Motoko Naitoh, Shigehiko Suzuki, Tsuneyoshi Seki, Kazuhiro Kobayashi, Tatsushi Toda, Ryuji Kaji, Ryōsuke Takahashi, Haruhisa Inoue
Abstract
Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia.