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Brandon Bumbaca, Marc R Birtwistle, James M Gallo
Glioblastoma Multiforme (GBM) remains a particularly difficult cancer to treat, and survival outcomes remain poor. In addition to the lack of dedicated drug discovery programs for GBM, extensive intratumor heterogeneity and epigenetic plasticity related to cell-state transitions are major roadblocks to successful drug therapy in GBM. To study these phenomenon, publicly available snRNAseq and bulk RNAseq data from patient samples were used to categorize cells from patients into four cell states (i.e. phenotypes), namely: (i) neural progenitor-like (NPC-like), (ii) oligodendrocyte progenitor-like (OPC-like), (iii) astrocyte-like (AC-like), and (iv) mesenchymal-like (MES-like)...
May 10, 2024: bioRxiv
#2
JOURNAL ARTICLE
Ye Hong, Christel Sourander, Benjamin Hackl, Jedidiah S Patton, Jismi John, Ilkka Paatero, Eleanor Coffey
Current treatments for anxiety and depression show limited efficacy in many patients, indicating the need for further research into the underlying mechanisms. JNK1 has been shown to regulate anxiety- and depressive-like behaviours in mice, however the effectors downstream of JNK1 are not known. Here we compare the phosphoproteomes from wild-type and Jnk1-/- mouse brains and identify JNK1-regulated signalling hubs. We next employ a zebrafish (Danio rerio) larvae behavioural assay to identify an antidepressant- and anxiolytic-like (AA) phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs...
May 15, 2024: Scientific Reports
#3
JOURNAL ARTICLE
Carissa Chen, Scott Lee, Katherine G Zyner, Milan Fernando, Victoria Nemeruck, Emilie Wong, Lee L Marshall, Jesse R Wark, Nader Aryamanesh, Patrick P L Tam, Mark E Graham, Anai Gonzalez-Cordero, Pengyi Yang
Defining the molecular networks orchestrating human brain formation is crucial for understanding neurodevelopment and neurological disorders. Challenges in acquiring early brain tissue have incentivized the use of three-dimensional human pluripotent stem cell (hPSC)-derived neural organoids to recapitulate neurodevelopment. To elucidate the molecular programs that drive this highly dynamic process, here, we generate a comprehensive trans-omic map of the phosphoproteome, proteome, and transcriptome of the exit of pluripotency and neural differentiation toward human cerebral organoids (hCOs)...
May 14, 2024: Cell Reports
#4
JOURNAL ARTICLE
Cathy Pichol-Thievend, Oceane Anezo, Aafrin M Pettiwala, Guillaume Bourmeau, Remi Montagne, Anne-Marie Lyne, Pierre-Olivier Guichet, Pauline Deshors, Alberto Ballestín, Benjamin Blanchard, Juliette Reveilles, Vidhya M Ravi, Kevin Joseph, Dieter H Heiland, Boris Julien, Sophie Leboucher, Laetitia Besse, Patricia Legoix, Florent Dingli, Stephane Liva, Damarys Loew, Elisa Giani, Valentino Ribecco, Charita Furumaya, Laura Marcos-Kovandzic, Konstantin Masliantsev, Thomas Daubon, Lin Wang, Aaron A Diaz, Oliver Schnell, Jürgen Beck, Nicolas Servant, Lucie Karayan-Tapon, Florence M G Cavalli, Giorgio Seano
Glioblastoma (GBM) is a highly lethal type of cancer. GBM recurrence following chemoradiation is typically attributed to the regrowth of invasive and resistant cells. Therefore, there is a pressing need to gain a deeper understanding of the mechanisms underlying GBM resistance to chemoradiation and its ability to infiltrate. Using a combination of transcriptomic, proteomic, and phosphoproteomic analyses, longitudinal imaging, organotypic cultures, functional assays, animal studies, and clinical data analyses, we demonstrate that chemoradiation and brain vasculature induce cell transition to a functional state named VC-Resist (vessel co-opting and resistant cell state)...
April 29, 2024: Nature Communications
#5
JOURNAL ARTICLE
Jianzhi Jiang, Brent Wilkinson, Ilse Flores, Nicolas Hartel, Simeon R Mihaylov, Veronica A Clementel, Helen R Flynn, Fowsan S Alkuraya, Sila Ultanir, Nicholas A Graham, Marcelo P Coba
A large number of synaptic proteins have been recurrently associated with complex brain disorders. One of these proteins, the Traf and Nck interacting kinase (TNIK), is a postsynaptic density (PSD) signaling hub, with many variants reported in neurodevelopmental disorder (NDD) and psychiatric disease. While rodent models of TNIK dysfunction have abnormal spontaneous synaptic activity and cognitive impairment, the role of mutations found in patients with TNIK protein deficiency and TNIK protein kinase activity during early stages of neuronal and synapse development has not been characterized...
2024: Frontiers in Molecular Neuroscience
#6
JOURNAL ARTICLE
Paola Cruz Flores, Tasmia Ahmed, Julia Podgorski, Hannah R Ortiz, Paul R Langlais, Karthikeyan Mythreye, Nam Y Lee
βIV-spectrin is a membrane-associated cytoskeletal protein that maintains the structural stability of cell membranes and integral proteins such as ion channels and transporters. Its biological functions are best characterized in the brain and heart, although recently we discovered a fundamental new role in the vascular system. Using cellular and genetic mouse models, we reported that βIV-spectrin acts as a critical regulator of developmental and tumor-associated angiogenesis. βIV-spectrin was shown to selectively express in proliferating endothelial cells (EC) and suppress VEGF/VEGFR2 signaling by enhancing receptor internalization and degradation...
April 10, 2024: Biochemical and Biophysical Research Communications
#7
JOURNAL ARTICLE
Xiaoting Zhou, You-Kyung Lee, Xianting Li, Henry Kim, Carlos Sanchez-Priego, Xian Han, Haiyan Tan, Suiping Zhou, Yingxue Fu, Kerry Purtell, Qian Wang, Gay R Holstein, Beisha Tang, Junmin Peng, Nan Yang, Zhenyu Yue
Autophagy is a conserved, catabolic process essential for maintaining cellular homeostasis. Malfunctional autophagy contributes to neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we report a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and brain LC3-interactome reveals roles of neuronal autophagy in targeting proteins of multiple cellular organelles/pathways, including endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) for degradation...
April 10, 2024: Nature Communications
#8
JOURNAL ARTICLE
Hui-Yang Lei, Gui-Lin Pi, Ting He, Rui Xiong, Jing-Ru Lv, Jia-Le Liu, Dong-Qin Wu, Meng-Zhu Li, Kun Shi, Shi-Hong Li, Na-Na Yu, Yang Gao, Hui-Ling Yu, Lin-Yu Wei, Xin Wang, Qiu-Zhi Zhou, Pei-Lin Zou, Jia-Yang Zhou, Ying-Zhou Liu, Nai-Ting Shen, Jie Yang, Dan Ke, Qun Wang, Gong-Ping Liu, Xi-Fei Yang, Jian-Zhi Wang, Ying Yang
BACKGROUND: Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary. METHODS: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR...
March 11, 2024: Military Medical Research
#9
JOURNAL ARTICLE
Yan Gao, Juntong Li, Kaichao Hu, Shasha Wang, Songwei Yang, Qidi Ai, Jiaqing Yan
Traditional Chinese medicine has been utilized in China for approximately thousands of years in clinical settings to prevent Alzheimer's disease (AD) and enhance memory, despite the lack of a systematic exploration of its biological underpinnings. Exciting research has corroborated the beneficial effects of tetrahydroxy stilbene glycoside (TSG), an extract derived from Polygonum multiflorum, in delaying learning and memory impairment in a model that mimics AD. Therefore, the primary objective of this study is to investigate the major function of TSG upon protein regulation in AD...
March 8, 2024: Journal of Proteomics
#10
JOURNAL ARTICLE
Keith E Kennedy, Nicole Kerlero de Rosbo, Antonio Uccelli, Maria Cellerino, Federico Ivaldi, Paola Contini, Raffaele De Palma, Hanne F Harbo, Tone Berge, Steffan D Bos, Einar A Høgestøl, Synne Brune-Ingebretsen, Sigrid A de Rodez Benavent, Friedemann Paul, Alexander U Brandt, Priscilla Bäcker-Koduah, Janina Behrens, Joseph Kuchling, Susanna Asseyer, Michael Scheel, Claudia Chien, Hanna Zimmermann, Seyedamirhosein Motamedi, Josef Kauer-Bonin, Julio Saez-Rodriguez, Melanie Rinas, Leonidas G Alexopoulos, Magi Andorra, Sara Llufriu, Albert Saiz, Yolanda Blanco, Eloy Martinez-Heras, Elisabeth Solana, Irene Pulido-Valdeolivas, Elena H Martinez-Lapiscina, Jordi Garcia-Ojalvo, Pablo Villoslada
Complex diseases such as Multiple Sclerosis (MS) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to the full organism. In fact, any phenotype for an organism is dictated by the interplay among these scales. We conducted a multilayer network analysis and deep phenotyping with multi-omics data (genomics, phosphoproteomics and cytomics), brain and retinal imaging, and clinical data, obtained from a multicenter prospective cohort of 328 patients and 90 healthy controls...
February 2024: PLoS Computational Biology
#11
JOURNAL ARTICLE
Dong Yang, Yu Wang, Tianbo Qi, Xi Zhang, Leyao Shen, Jingrui Ma, Zhengyuan Pang, Neeraj K Lal, Daniel B McClatchy, Saba Heydari Seradj, Verina H Leung, Kristina Wang, Yi Xie, Filip S Polli, Anton Maximov, Oscar Christian Gonzalez, Luis de Lecea, Hollis T Cline, Vineet Augustine, John R Yates, Li Ye
For decades, the expression of immediate early genes (IEGs) such as FOS has been the most widely used molecular marker representing neuronal activation. However, to date, there is no equivalent surrogate available for the decrease of neuronal activity. Here, we developed an optogenetic-based biochemical screen in which population neural activities can be controlled by light with single action potential precision, followed by unbiased phosphoproteomic profiling. We identified that the phosphorylation of pyruvate dehydrogenase (pPDH) inversely correlated with the intensity of action potential firing in primary neurons...
January 17, 2024: Neuron
#12
Kenny K H Yu, Sreyashi Basu, Gerard Baquer, Ryuhjin Ahn, Jennifer Gantchev, Sonali Jindal, Michael S Regan, Zaki Abou-Mrad, Michael C Prabhu, Marc J Williams, Alicia D D'Souza, Seth W Malinowski, Kelsey Hopland, Yuval Elhanati, Sylwia A Stopka, Alexei Stortchevoi, Zhong He, Jingjing Sun, Yulong Chen, Alexsandra B Espejo, Kin Hoe Chow, Smitha Yerrum, Pei-Lun Kao, Brittany Parker Kerrigan, Lisa Norberg, Douglas Nielsen, Vinay K Puduvalli, Jason Huse, Rameen Beroukhim, Yon Son Betty Kim, Sangeeta Goswami, Adrienne Boire, Sarah Frisken, Michael J Cima, Matthias Holdhoff, Calixto-Hope G Lucas, Chetan Bettegowda, Stuart S Levine, Tejus A Bale, Cameron Brennan, David A Reardon, Frederick F Lang, E Antonio Chiocca, Keith L Ligon, Forest M White, Padmanee Sharma, Viviane Tabar, Nathalie Y R Agar
UNLABELLED: Glioblastoma (GBM) is a primary brain cancer with an abysmal prognosis and few effective therapies. The ability to investigate the tumor microenvironment before and during treatment would greatly enhance both understanding of disease response and progression, as well as the delivery and impact of therapeutics. Stereotactic biopsies are a routine surgical procedure performed primarily for diagnostic histopathologic purposes. The role of investigative biopsies - tissue sampling for the purpose of understanding tumor microenvironmental responses to treatment using integrated multi-modal molecular analyses ('Multi-omics") has yet to be defined...
December 31, 2023: medRxiv
#13
JOURNAL ARTICLE
Y Ito, S Takeda, T Nakajima, A Oyama, H Takeshita, K Miki, Y Takami, Y Takeya, M Shimamura, H Rakugi, R Morishita
BACKGROUND: Epidemiological evidence has demonstrated a clear association between diabetes mellitus and increased risk of Alzheimer's disease (AD). Cerebral accumulation of phosphorylated tau aggregates, a cardinal neuropathological feature of AD, is associated with neurodegeneration and cognitive decline. Clinical and experimental studies indicate that diabetes mellitus affects the development of tau pathology; however, the underlying molecular mechanisms remain unknown. OBJECTIVE: In the present study, we used a unique diabetic AD mouse model to investigate the changes in tau phosphorylation patterns occurring in the diabetic brain...
2024: Journal of Prevention of Alzheimer's Disease
#14
JOURNAL ARTICLE
Bekir Altas, Liam P Tuffy, Annarita Patrizi, Kalina Dimova, Tolga Soykan, Cheryl Brandenburg, Andrea J Romanowski, Julia R Whitten, Colin D Robertson, Saovleak N Khim, Garrett W Crutcher, Mateusz C Ambrozkiewicz, Oleksandr Yagensky, Dilja Krueger-Burg, Matthieu Hammer, He-Hsuan Hsiao, Pawel R Laskowski, Lydia Dyck, Adam C Puche, Marco Sassoè-Pognetto, John J E Chua, Henning Urlaub, Olaf Jahn, Nils Brose, Alexandros Poulopoulos
BACKGROUND: Neuroligin-3 is a postsynaptic adhesion molecule involved in synapse development and function. It is implicated in rare, monogenic forms of autism, and its shedding is critical to the tumor microenvironment of gliomas. While other members of the Neuroligin family exhibit synapse-type specificity in localization and function through distinct interactions with postsynaptic scaffold proteins, the specificity of Neuroligin-3 synaptic localization remains largely unknown. METHODS: We investigated the synaptic localization of Neuroligin-3 across regions in mouse and human brain samples after validating antibody specificity in knockout animals...
December 26, 2023: Biological Psychiatry
#15
JOURNAL ARTICLE
Magi Andorra, Ana Freire, Irati Zubizarreta, Nicole Kerlero de Rosbo, Steffan D Bos, Melanie Rinas, Einar A Høgestøl, Sigrid A de Rodez Benavent, Tone Berge, Synne Brune-Ingebretse, Federico Ivaldi, Maria Cellerino, Matteo Pardini, Gemma Vila, Irene Pulido-Valdeolivas, Elena H Martinez-Lapiscina, Sara Llufriu, Albert Saiz, Yolanda Blanco, Eloy Martinez-Heras, Elisabeth Solana, Priscilla Bäcker-Koduah, Janina Behrens, Joseph Kuchling, Susanna Asseyer, Michael Scheel, Claudia Chien, Hanna Zimmermann, Seyedamirhosein Motamedi, Josef Kauer-Bonin, Alex Brandt, Julio Saez-Rodriguez, Leonidas G Alexopoulos, Friedemann Paul, Hanne F Harbo, Hengameh Shams, Jorge Oksenberg, Antonio Uccelli, Ricardo Baeza-Yates, Pablo Villoslada
BACKGROUND: Multiple sclerosis patients would benefit from machine learning algorithms that integrates clinical, imaging and multimodal biomarkers to define the risk of disease activity. METHODS: We have analysed a prospective multi-centric cohort of 322 MS patients and 98 healthy controls from four MS centres, collecting disability scales at baseline and 2 years later. Imaging data included brain MRI and optical coherence tomography, and omics included genotyping, cytomics and phosphoproteomic data from peripheral blood mononuclear cells...
December 22, 2023: Journal of Neurology
#16
JOURNAL ARTICLE
Marisol Sampedro-Castañeda, Lucas L Baltussen, André T Lopes, Yichen Qiu, Liina Sirvio, Simeon R Mihaylov, Suzanne Claxton, Jill C Richardson, Gabriele Lignani, Sila K Ultanir
Developmental and epileptic encephalopathies (DEEs) are a group of rare childhood disorders characterized by severe epilepsy and cognitive deficits. Numerous DEE genes have been discovered thanks to advances in genomic diagnosis, yet putative molecular links between these disorders are unknown. CDKL5 deficiency disorder (CDD, DEE2), one of the most common genetic epilepsies, is caused by loss-of-function mutations in the brain-enriched kinase CDKL5. To elucidate CDKL5 function, we looked for CDKL5 substrates using a SILAC-based phosphoproteomic screen...
December 11, 2023: Nature Communications
#17
Xian Chen, Ling Xie, Ryan Sheehy, Yan Xiong, Adil Muneer, John Wrobel, Kwang-Su Park, Jing Liu, Julia Velez, Yanjia Luo, Ya-Dong Li, Luis Quintanilla, Yongyi Li, Chongchong Xu, Zhexing Wen, Juan Song, Jian Jin, Mohanish Deshmukh
Current amyloid beta-targeting approaches for Alzheimer's disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism...
November 21, 2023: Research Square
#18
Noah M Lancaster, Pavel Sinitcyn, Patrick Forny, Trenton M Peters-Clarke, Caroline Fecher, Andrew J Smith, Evgenia Shishkova, Tabiwang N Arrey, Anna Pashkova, Margaret Lea Robinson, Nicholas Arp, Jing Fan, Juli Hansen, Andrea Galmozzi, Lia R Serrano, Michael S Westphall, Hamish Stewart, Christian Hock, Eugen Damoc, David J Pagliarini, Vlad Zabrouskov, Joshua J Coon
As a key mechanism for cellular signal transduction, protein phosphorylation plays critical roles in myriad cellular processes. This modification, however, is highly dynamic and occurs at sub-stoichiometric levels. Mass spectrometry is an essential tool for studying this modification on a global scale; however, the technology's impact suffers from four main limitations: need for site localization, dynamic range, reproducibility, and throughput. Here we describe the use of a novel mass spectrometer (Orbitrap Astral) coupled with data-independent acquisition (DIA) to achieve detection of close to 40,000 unique phosphorylation sites within one hour of analysis...
November 21, 2023: bioRxiv
#19
JOURNAL ARTICLE
Yuanxuan Huang, Xianfeng Shao, Yuanyuan Liu, Kehan Yan, Wantao Ying, Fuchu He, Dongxue Wang
Global phosphoproteome profiling can provide insights into cellular signaling and disease pathogenesis. To achieve comprehensive phosphoproteomic analyses with minute quantities of material, we developed a rapid and sensitive phosphoproteomics sample preparation strategy based on ultrasound. We found that ultrasonication-assisted digestion can significantly improve peptide identification by 20% due to the generation of longer peptides that can be detected by mass spectrometry. By integrating this rapid ultrasound-assisted peptide-identification-enhanced proteomic method (RUPE) with streamlined phosphopeptide enrichment steps, we established RUPE-phospho, a fast and efficient strategy to characterize protein phosphorylation in mass-limited samples...
November 27, 2023: Analytical Chemistry
#20
JOURNAL ARTICLE
Ting Fan, Peng-Fei Guan, Xiao-Fang Zhong, Meng-Ya Xiang, Ying-Qiu Peng, Ruo-Qiao Zhou, Jia-Min Gong, Yu-Qing Zheng, A-Qiang Dai, Jia-Ling Feng, Hong-Zhe Yu, Jian Li, Hua-Wei Li, Yun-Feng Wang
Compared with individuals with hearing loss, tinnitus patients without hearing loss have more psychological or emotional problems. Tinnitus is closely associated to abnormal metabolism and function of the limbic system, a key brain region for emotion experience, but the underlying molecular mechanism remains unknown. Using whole-brain microvasculature dynamics imaging, the anterior cingulate cortex (ACC) is identified as a key brain region of limbic system involve in the onset of salicylate-induced tinnitus in mice...
November 27, 2023: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
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