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611.
Nirma D. Perera Rebecca K. Sheean Chew L. Lau Yea Seul Shin Philip M. Beart Malcolm K. Horne 《Autophagy》2018,14(3):534-551
Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is compromised in neurodegenerative disorders, which may contribute to cytoplasmic sequestration of aggregation-prone and toxic proteins in neurons. Genetic or pharmacological modulation of autophagy to promote clearance of misfolded proteins may be a promising therapeutic avenue for these disorders. Here, we demonstrate robust autophagy induction in motor neuronal cells expressing SOD1 or TARDBP/TDP-43 mutants linked to amyotrophic lateral sclerosis (ALS). Treatment of these cells with rilmenidine, an anti-hypertensive agent and imidazoline-1 receptor agonist that induces autophagy, promoted autophagic clearance of mutant SOD1 and efficient mitophagy. Rilmenidine administration to mutant SOD1G93A mice upregulated autophagy and mitophagy in spinal cord, leading to reduced soluble mutant SOD1 levels. Importantly, rilmenidine increased autophagosome abundance in motor neurons of SOD1G93A mice, suggesting a direct action on target cells. Despite robust induction of autophagy in vivo, rilmenidine worsened motor neuron degeneration and symptom progression in SOD1G93A mice. These effects were associated with increased accumulation and aggregation of insoluble and misfolded SOD1 species outside the autophagy pathway, and severe mitochondrial depletion in motor neurons of rilmenidine-treated mice. These findings suggest that rilmenidine treatment may drive disease progression and neurodegeneration in this mouse model due to excessive mitophagy, implying that alternative strategies to beneficially stimulate autophagy are warranted in ALS. 相似文献
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Macroautophagy (hereafter autophagy) initiates at the phagophore assembly site (PAS), where most of the AuTophaGy-related (Atg) proteins are at least transiently localized. As the first protein complex targeted to the PAS, the Atg17-Atg31-Atg29 complex serves as the scaffold for other Atg proteins and plays a critical role for the organization of the PAS, and in autophagy initiation. We recently showed that this complex is constitutively formed and activated by the phosphorylation of Atg29 when autophagy is induced. Phosphorylation of Atg29 is required for its interaction with Atg11, another scaffold protein, and its function for promoting the proper assembly of the PAS. Single-particle electron microscopy analysis of the Atg17-Atg31-Atg29 complex reveals an elongated structure with Atg29 located at the opposing ends. This structural arrangement allows Atg29 to interact with Atg11, and is critical in the organization of the intact Atg1 complex. 相似文献
615.
Wen-Yee Chay Sung-Hock Chew Whee-Sze Ong Inny Busmanis Xinyun Li Sharyl Thung Lynette Ngo Sheow- Lei Lim Yong-Kuei Lim Yin-Nin Chia Elisa Koh Cindy Pang Lay-Tin Soh Jin Wang Tew-Hong Ho Sun-Kuie Tay Soo-Kim Lim-Tan Kiat-Hon Lim John Whay-Kuang Chia Liang-Kee Goh 《PloS one》2013,8(4)
Mucinous epithelial ovarian cancer has a poor prognosis in the advanced stages and responds poorly to conventional chemotherapy. We aim to elucidate the clinicopathological factors and incidence of HER2 expression of this cancer in a large Asian retrospective cohort from Singapore. Of a total of 133 cases, the median age at diagnosis was 48.3 years (range, 15.8–89.0 years), comparatively younger than western cohorts. Most were Chinese (71%), followed by Malays (16%), others (9.0%), and Indians (5%). 24% were noted to have a significant family history of malignancy of which breast and gastrointestinal cancers the most prominent. Majority of the patients (80%) had stage I disease at diagnosis. Information on HER2 status was available in 113 cases (85%). Of these, 31 cases (27.4%) were HER2+, higher than 18.8% reported in western population. HER2 positivity appeared to be lower among Chinese and higher among Malays patients (p = 0.052). With the current standard of care, there was no discernible impact of HER2 status on overall survival. (HR = 1.79; 95% CI, 0.66–4.85; p = 0.249). On the other hand, positive family history of cancer, presence of lymphovascular invasion, and ovarian surface involvements were significantly associated with inferior overall survival on univariate and continued to be statistically significant after adjustment for stage. While these clinical factors identify high risk patients, it is promising that the finding of a high incidence of HER2 in our Asian population may allow development of a HER2 targeted therapy to improve the management of mucinous ovarian cancers. 相似文献
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Joery den Hoed Elke de Boer Norine Voisin Alexander J.M. Dingemans Nicolas Guex Laurens Wiel Christoffer Nellaker Shivarajan M. Amudhavalli Siddharth Banka Frederique S. Bena Bruria Ben-Zeev Vincent R. Bonagura Ange-Line Bruel Theresa Brunet Han G. Brunner Hui B. Chew Jacqueline Chrast Loreta Cimbalistienė Lisenka E.L.M. Vissers 《American journal of human genetics》2021,108(2):346-356
620.
Carolina Courage Karen L. Oliver Eon Joo Park Jillian M. Cameron Kariona A. Grabińska Mikko Muona Laura Canafoglia Antonio Gambardella Edith Said Zaid Afawi Betul Baykan Christian Brandt Carlo di Bonaventura Hui Bein Chew Chiara Criscuolo Leanne M. Dibbens Barbara Castellotti Patrizia Riguzzi Anna-Elina Lehesjoki 《American journal of human genetics》2021,108(4):722-738