Nature aging · 2023
LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Li Dan, Johmura Yoshikazu, Morimoto Satoru, Doi Miyuki, Nakanishi Keiko, Ozawa Manabu, Tsunekawa Yuji, Inoue-Yamauchi Akane, Naruse Hiroya, Matsukawa Takashi, Takeshita Yukio, Suzuki Naoki, Aoki Masashi, Nishiyama Ayumi, Zeng Xin, Konishi Chieko, Suzuki Narumi, Nishiyama Atsuya, Harris Alexander Stephen, Morita Mariko, Yamaguchi Kiyoshi, Furukawa Yoichi, Nakai Kenta, Tsuji Shoji, Yamazaki Satoshi, Yamanashi Yuji, Shimada Shoichi, Okada Takashi, Okano Hideyuki, Toda Tatsushi, Nakanishi Makoto
Аннотация
Protein misfolding is a major factor of neurodegenerative diseases. Post-mitotic neurons are highly susceptible to protein aggregates that are not diluted by mitosis. Therefore, post-mitotic cells may have a specific protein quality control system. Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons. LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins. Lonrf2-/- mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia. Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture. The shortening of neurites in MNs from patients with amyotrophic lateral sclerosis is rescued by ectopic expression of LONRF2. Our findings reveal that LONRF2 is a protein quality control ligase whose loss may contribute to MN degeneration and motor deficits.