دورية أكاديمية
Conformational change of RNA-helicase DHX30 by ALS/FTD-linked FUS induces mitochondrial dysfunction and cytosolic aggregates
العنوان: | Conformational change of RNA-helicase DHX30 by ALS/FTD-linked FUS induces mitochondrial dysfunction and cytosolic aggregates |
---|---|
المؤلفون: | Ryota Hikiami, Toshifumi Morimura, Takashi Ayaki, Tomoyuki Tsukiyama, Naoko Morimura, Makiko Kusui, Hideki Wada, Sumio Minamiyama, Akemi Shodai, Megumi Asada-Utsugi, Shin-ichi Muramatsu, Takatoshi Ueki, Ryosuke Takahashi, Makoto Urushitani |
المصدر: | Scientific Reports, Vol 12, Iss 1, Pp 1-15 (2022) |
بيانات النشر: | Nature Portfolio, 2022. |
سنة النشر: | 2022 |
المجموعة: | LCC:Medicine LCC:Science |
مصطلحات موضوعية: | Medicine, Science |
الوصف: | Abstract Genetic mutations in fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS). Although mitochondrial dysfunction and stress granule have been crucially implicated in FUS proteinopathy, the molecular basis remains unclear. Here, we show that DHX30, a component of mitochondrial RNA granules required for mitochondrial ribosome assembly, interacts with FUS, and plays a crucial role in ALS-FUS. WT FUS did not affect mitochondrial localization of DHX30, but the mutant FUS lowered the signal of mitochondrial DHX30 and promoted the colocalization of cytosolic FUS aggregates and stress granule markers. The immunohistochemistry of the spinal cord from an ALS-FUS patient also confirmed the colocalization, and the immunoelectron microscope demonstrated decreased mitochondrial DHX30 signal in the spinal motor neurons. Subcellular fractionation by the detergent-solubility and density-gradient ultracentrifugation revealed that mutant FUS also promoted cytosolic mislocalization of DHX30 and aggregate formation. Interestingly, the mutant FUS disrupted the DHX30 conformation with aberrant disulfide formation, leading to impaired mitochondrial translation. Moreover, blue-native gel electrophoresis revealed an OXPHOS assembly defect caused by the FUS mutant, which was similar to that caused by DHX30 knockdown. Collectively, our study proposes DHX30 as a pivotal molecule in which disulfide-mediated conformational change mediates mitochondrial dysfunction and cytosolic aggregate formation in ALS-FUS. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 2045-2322 34928774 |
Relation: | https://doaj.org/toc/2045-2322 |
DOI: | 10.1038/s41598-022-20405-2 |
URL الوصول: | https://doaj.org/article/466c0b9b2b744c3492877408d329cf97 |
رقم الأكسشن: | edsdoj.466c0b9b2b744c3492877408d329cf97 |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 20452322 34928774 |
---|---|
DOI: | 10.1038/s41598-022-20405-2 |