Tao Z.,Jiangsu Key Laboratory of Translational Research and Therapy for Neuro Psycho Diseases |
Wang H.,Jiangsu Key Laboratory of Translational Research and Therapy for Neuro Psycho Diseases |
Xia Q.,Jiangsu Key Laboratory of Translational Research and Therapy for Neuro Psycho Diseases |
Li K.,Jiangsu Key Laboratory of Translational Research and Therapy for Neuro Psycho Diseases |
And 5 more authors.
Human Molecular Genetics
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are the two common neurodegenerative diseases that have been associated with the GGGGCC·GGCCCC repeat RNA expansion in a noncoding region of C9orf72. It has been previously reported that unconventional repeat-associated non-ATG (RAN) translation of GGGGCC·GGCCCC repeats produces five types of dipeptide-repeat proteins (referred to as RAN proteins): poly-glycine-alanine (GA), poly-glycine-proline (GP), poly-glycinearginine (GR), poly-proline-arginine (PR) and poly-proline-alanine (PA). Although protein aggregates of RAN proteins have been found in patients, it is unclear whether RAN protein aggregation induces neurotoxicity. In the present study, we aimed to understand the biological properties of all five types of RAN proteins. Surprisingly, our results showed that none of these RAN proteins was aggregate-prone in our cellular model and that the turnover of these RAN proteins was not affected by the ubiquitin-proteasome system or autophagy. Moreover, poly-GR and poly-PR, but not poly-GA, poly-GP or poly-PA, localized to the nucleolus and induced the translocation of the key nucleolar component nucleophosmin, leading to nucleolar stress and cell death. This poly-GR- and poly-PR-mediated defect in nucleolar function was associated with the suppression of ribosomal RNAsynthesis and the impairment of stress granule formation. Taken together, the results of the present study suggest a simple model of the molecular mechanisms underlying RAN translation-mediated cytotoxicity in C9orf72-linked ALS/FTD in which nucleolar stress, but not protein aggregation, is the primary contributor to C9orf72-linked neurodegeneration. © The Author 2015. Source
Xu R.,University of Chinese Academy of Sciences |
Hu Q.,Jiangsu Key Laboratory of Translational Research and Therapy for Neuro Psycho Diseases |
Ma Q.,Jiangsu Key Laboratory of Translational Research and Therapy for Neuro Psycho Diseases |
Liu C.,Soochow University of China |
And 2 more authors.
Cell Death and Disease
Loss of the mitochondrial protease activity of Omi causes mitochondrial dysfunction, neurodegeneration with parkinsonian features and premature death in mnd2 (motor neuron degeneration 2) mice. However, the detailed mechanisms underlying this pathology remain largely unknown. Here, we report that Omi participates in the process of mitochondrial biogenesis, which has been linked to several neurodegenerative diseases. The mitochondrial biogenesis is deficit in mnd2 mice, evidenced by severe decreases of mitochondrial components, mitochondrial DNA and mitochondrial density. Omi cleaves glycogen synthase kinase 3β (GSK3β), a kinase promoting PPARγ coactivator-1α (PGC-1α) degradation, to regulate PGC-1α, a factor important for the mitochondrial biogenesis. In mnd2 mice, GSK3β abundance is increased and PGC-1α abundance is decreased significantly. Inhibition of GSK3β by SB216763 or overexpression of PGC-1α can restore mitochondrial biogenesis in mnd2 mice or Omi-knockdown N2a cells. Furthermore, there is a significant improvement of the movement ability of mnd2 mice after SB216763 treatment. Thus, our study identified Omi as a novel regulator of mitochondrial biogenesis, involving in Omi protease-deficient-induced neurodegeneration. © 2014 Macmillan Publishers Limited All rights reserved. Source
Shi M.,Jiangsu Key Laboratory of Translational Research and Therapy for Neuro Psycho Diseases |
Cheng L.,Soft Science |
Zhang Z.,Jiangsu Key Laboratory of Translational Research and Therapy for Neuro Psycho Diseases |
Liu Z.,Soft Science |
And 2 more authors.
International Journal of Nanomedicine
Magnetic iron oxide nanoparticles (NPs) are emerging as novel materials with great potentials for various biomedical applications, but their biological activities are largely unknown. In the present study, we found that ferroferric oxide nanoparticles (Fe3O4 NPs) induced autophagy in blood cells. Both naked and modifed Fe3O4 NPs induced LC3 lipidation and degraded p62, a monitor of autophagy flux. And this change could be abolished by autophagy inhibitors. Mechanistically, Fe3O4 NP-induced autophagy was accompanied by increased Beclin 1 and VPS34 and decreased Bcl-2, thus promoting the formation of the critical complex in autophagy initiation. Further studies demonstrated that Fe3O4 NPs attenuated cell death induced by anticancer drugs bortezomib and doxorubicin. Therefore, this study suggested that Fe3O4 NPs can induce prosurvival autophagy in blood cells by modulating the Beclin l/Bcl-2/VPS34 complex. This study suggests that caution should be taken when Fe3O4 NPs are used in blood cancer patients. © 2015 Shi et al Source