Nature Neuroscience

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ISSN / EISSN : 1097-6256 / 1546-1726
Published by: Springer Nature (10.1038)
Total articles ≅ 6,663
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Kornélia Szebényi, Léa M. D. Wenger, Yu Sun, Alexander W. E. Dunn, Colleen A. Limegrover, George M. Gibbons, Elena Conci, , , , et al.
Published: 21 October 2021
Nature Neuroscience pp 1-13; https://doi.org/10.1038/s41593-021-00923-4

Abstract:
Amyotrophic lateral sclerosis overlapping with frontotemporal dementia (ALS/FTD) is a fatal and currently untreatable disease characterized by rapid cognitive decline and paralysis. Elucidating initial cellular pathologies is central to therapeutic target development, but obtaining samples from presymptomatic patients is not feasible. Here, we report the development of a cerebral organoid slice model derived from human induced pluripotent stem cells (iPSCs) that recapitulates mature cortical architecture and displays early molecular pathology of C9ORF72 ALS/FTD. Using a combination of single-cell RNA sequencing and biological assays, we reveal distinct transcriptional, proteostasis and DNA repair disturbances in astroglia and neurons. We show that astroglia display increased levels of the autophagy signaling protein P62 and that deep layer neurons accumulate dipeptide repeat protein poly(GA), DNA damage and undergo nuclear pyknosis that could be pharmacologically rescued by GSK2606414. Thus, patient-specific iPSC-derived cortical organoid slice cultures are a reproducible translational platform to investigate preclinical ALS/FTD mechanisms as well as novel therapeutic approaches.
, Josephine Lampe, , Raphael Schuster, , Kristin Müller, , , Linlin Zhang, Ümit Özorhan, et al.
Published: 21 October 2021
Nature Neuroscience pp 1-12; https://doi.org/10.1038/s41593-021-00926-1

Abstract:
Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
Tamara Markovic, Christian E. Pedersen, Nicolas Massaly, Yvan M. Vachez, Brian Ruyle, Caitlin A. Murphy, Kavitha Abiraman, Jung Hoon Shin, Jeniffer J. Garcia, Hye Jean Yoon, et al.
Published: 18 October 2021
Nature Neuroscience pp 1-13; https://doi.org/10.1038/s41593-021-00924-3

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Xian Zhang, Wuqiang Guan, Tao Yang, Alessandro Furlan, Xiong Xiao, , Xu An, William Galbavy, , , et al.
Published: 18 October 2021
Nature Neuroscience pp 1-15; https://doi.org/10.1038/s41593-021-00927-0

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Renchao Chen, Timothy R. Blosser, , Junjie Hao, Aritra Bhattacherjee, Wenqiang Chen, Luis M. Tuesta, ,
Published: 18 October 2021
Nature Neuroscience pp 1-15; https://doi.org/10.1038/s41593-021-00938-x

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Anes Ju,
Published: 15 October 2021
Nature Neuroscience pp 1-2; https://doi.org/10.1038/s41593-021-00945-y

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Clare R. Quirk, , Sunandha Srikanth, Maylin L. Fu, Naomie Devico Marciano, Morgan K. Wright, Darian F. Parsey, Stanley Liu, Rachel E. Siretskiy, Tiffany L. Huynh, et al.
Published: 4 October 2021
Nature Neuroscience pp 1-14; https://doi.org/10.1038/s41593-021-00919-0

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