Review
Biochemistry & Molecular Biology
Divya M. Teli, Anuradha K. Gajjar
Summary: Elevated glucose level due to β-cell dysfunction is a key marker of Type-II diabetes. GSK-3, an enzyme involved in glycogen metabolism control, has been explored for its potential as a target for diabetes treatment. This review article examines the structural analysis and molecular modeling of GSK-3, as well as advancements in the development of GSK-3 inhibitors as potential therapeutics for Type II diabetes.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Fisheries
Xiaotong Sun, Hongtao Nie, Xiwu Yan
Summary: This study identified and investigated three novel glycogen metabolism-related proteins in Manila clam, suggesting their potential involvement in innate immunity and important role in immune defense.
Review
Biochemistry & Molecular Biology
Prachi Umbarkar, Sulivette Y. Ruiz Ramirez, Angelica Toro Cora, Sultan Tousif, Hind Lal
Summary: This article focuses on the isoform-specific roles of GSK-3 in the pathophysiology of cardiometabolic disorders. GSK-3α plays a critical role in promoting adverse fibrotic remodeling and deterioration of cardiac function, while GSK-3β has the opposite effect in cardiac fibrosis. Inhibition of both GSK-3 isoforms shows benefits against obesity-associated cardiometabolic pathologies, and the molecular interactions with other signaling pathways are discussed. The article also reviews the limitations and potential applications of small molecule inhibitors targeting GSK-3 for the treatment of metabolic disorders.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Article
Integrative & Complementary Medicine
Hei-Jen Huang, Jie-Ling Chen, Jian-Fu Liao, Yu-Hsin Chen, Min-Wei Chieu, Ya-Yun Ke, Chih-Chieh Hsu, Ying-Chieh Tsai, Hsiu Mei Hsieh-Li
Summary: This study evaluated the beneficial effects of the psychobiotic PS128 in AD mice and found that PS128 effectively prevented damage induced by intracerebroventricular injection of streptozotocin by regulating propionic acid levels, glycogen synthase kinase 3 beta activity, and gliosis. PS128 supplementation is suggested as a potential strategy to prevent and/or delay the progression of AD.
BMC COMPLEMENTARY MEDICINE AND THERAPIES
(2021)
Review
Biochemistry & Molecular Biology
Chia-Ling Chen, Po-Chun Tseng, Rahmat Dani Satria, Thi Thuy Nguyen, Cheng-Chieh Tsai, Chiou-Feng Lin
Summary: GSK-3 is a vital regulator of glycogen synthesis that plays a crucial role in cellular bioregulation. Abnormal GSK-3 activation and inactivation can lead to liver damage. Targeting GSK-3 with drugs is a potential therapeutic approach for liver protection. Additionally, blocking GSK-3 has a protective effect in IFN-gamma-mediated immune hepatitis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Parisa Badiee, Michelle F. Maritz, Benjamin Thierry
Summary: A nanoformulation of a small molecule GSK3 inhibitor has been developed as a potential alternative to antibody-based checkpoint inhibition. The nanoformulation efficiently inhibits PD-1 expression and improves the survival and proliferation of CAR-T cells, while also increasing the population of memory T cells.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2022)
Article
Cell Biology
S. Grace Herod, Annie Dyatel, Stefanie Hodapp, Marko Jovanovic, Luke E. Berchowitz
Summary: Amyloids play important roles in age-related diseases. Some cells use reversible amyloid-like structures for translational control. Yeast 14-3-3 proteins bind to amyloid-like assemblies and facilitate their clearance, contributing to global protein aggregate homeostasis. These findings suggest that 14-3-3 proteins may protect against pathological protein aggregates.
Article
Clinical Neurology
M. H. D. Rami Al Shweiki, Patrick Oeckl, Adrian Pachollek, Petra Steinacker, Peggy Barschke, Steffen Halbgebauer, Sarah Anderl-Straub, Jan Lewerenz, Albert C. Ludolph, Georg Bernhard Landwehrmeyer, Markus Otto
Summary: PDYN-derived peptides were found to be substantially decreased in the CSF of HD patients, while NfL levels were elevated, indicating that PDYN-derived peptides may be a more specific biomarker for HD.
MOVEMENT DISORDERS
(2021)
Article
Multidisciplinary Sciences
Long He, Jennifer Endress, Sungyun Cho, Zhongchi Li, Yuxiang Zheng, John M. Asara, John Blenis
Summary: Serine/one-carbon metabolism plays a critical role in cancer cell growth, but the regulatory mechanisms are not well understood. This study reveals that glycogen synthase kinase 3 (GSK3) plays a key role in regulating the expression of serine/one-carbon metabolic enzymes. Inhibition of nuclear GSK3 signaling enhances the efficacy of serine/one-carbon metabolism inhibitors in suppressing cancer cell proliferation.
Review
Cell Biology
Ryan T. McCallum, Melissa L. Perreault
Summary: This study discussed the widespread multi-system involvement of GSK-3 in contributing to the neuropathology of MDD, emphasizing the feed-forward mechanistic links between all major neuronal signaling pathways.
Article
Biochemical Research Methods
Dan Wu, Xue Bai, Jiasi Yu, Linli Guo, Yanan Zhao, Ping Liu
Summary: Alzheimer's disease (AD) has caused a significant economic burden due to its prevalence and impact on society and families. A new glycogen synthase kinase-3 (GSK-3) inhibitor, PIMPC, with antioxidant and metal chelating properties, was designed and synthesized as a potential anti-AD compound. A quantitative HPLC method was established to determine the pharmacokinetics (PK) of PIMPC in rats, revealing fast absorption, rapid distribution, and elimination following intragastric administration. Additionally, PIMPC did not have adverse effects on liver and kidney function at therapeutic doses, supporting its potential as an anti-AD drug.
BIOMEDICAL CHROMATOGRAPHY
(2023)
Article
Biochemistry & Molecular Biology
Davoud Ghazanfari, Mahboubeh S. Noori, Stephen C. Bergmeier, Jennifer Hines, Kelly D. McCall, Douglas J. Goetz
Summary: COB-187 inhibits GSK3 beta via a specific, reversible, time and Cys-199-dependent mechanism, demonstrating high selectivity and potent activity against the target enzyme.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Clinical Neurology
Hae Nim Lee, Seung Jae Hyeon, Heejung Kim, Kyoung Mi Sim, Yunha Kim, Jeongmin Ju, Junghee Lee, Yingxiao Wang, Hoon Ryu, Jihye Seong
Summary: In Huntington's disease, reduced FAK and FA dynamics impair the formation of neurites, leading to synaptic dysfunctions. Mutant HTT associates with phosphatidylinositol 4,5-biphosphate, altering its distribution at the plasma membrane and inhibiting FAK activation.
ACTA NEUROPATHOLOGICA
(2022)
Article
Biochemistry & Molecular Biology
Chantalle Moolman, Rencia van der Sluis, Richard M. Beteck, Lesetja J. Legoabe
Summary: Plasmodium falciparum glycogen synthase kinase-3 (PfGSK-3) has been identified as a potential target for the development of novel drugs against multi-drug resistant malaria. A series of benzofuran-based compounds were synthesized and evaluated as inhibitors of PfGSK-3 and human glycogen synthase kinase-3 beta (HsGSK-3 beta). Among these compounds, five preferentially inhibited PfGSK-3, with four exhibiting IC50 values in the sub-micromolar range. Evaluation of the structure-activity relationships revealed potential for future design of PfGSK-3 selective inhibitors using chalcone-based scaffolds like benzofurans.
BIOORGANIC CHEMISTRY
(2021)
Article
Cell Biology
Ligia Fao, Patricia Coelho, Ricardo J. Rodrigues, A. Cristina Rego
Summary: This study explores the impact of altered Fyn levels in Huntington's disease (HD) on the function and localization of NMDA receptors (NMDARs) at the post-synaptic density (PSD), as well as their role in intracellular neuroprotective pathways and cell survival. The results demonstrate that decreased Fyn levels in HD mouse striatal neurons are associated with reduced phosphorylation of GluN2B-composed NMDARs at the synapse, along with increased activity of extrasynaptic NMDARs and induction of cell death pathways. Activation of Fyn restores NMDARs localization and function at the PSD, and promotes activation of neuroprotective pathways and cell survival in HD neurons.
Article
Biochemistry & Molecular Biology
Laura Valles-Saiz, Rocio Peinado-Cahuchola, Jesus Avila, Felix Hernandez
Summary: Tau, a cytoskeletal protein mainly expressed in neurons, plays important roles in multiple cellular processes. This study reveals that Tau4R is the main isoform of tau expressed in the kidney, particularly in podocytes. Knockout mice without tau display a more dynamic cytoskeleton in podocytes and exhibit glomerular damage and reduced urinary creatinine.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Neurosciences
Juan R. Perea, Marta Bolos, Raquel Cuadros, Esther Garcia, Vega Garcia-Escudero, Felix Hernandez, Roisin M. McManus, Michael T. Heneka, Jesus Avila
Summary: This study demonstrates that inhibiting p38 can attenuate the toxic effect of tau in microglia and enhance microglia-mediated tau phagocytosis.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Multidisciplinary Sciences
Juan R. Perea, Esther Garcia, Laura Valles-Saiz, Raquel Cuadros, Felix Hernandez, Marta Bolos, Jesus Avila
Summary: Tauopathies are neurodegenerative diseases characterized by the accumulation of hyperphosphorylated tau protein. Inflammation, particularly the activation of microglia, is also involved in these diseases. The p38 MAPK pathway, primarily expressed in glia, has been associated with tau phosphorylation in neurodegenerative diseases like Alzheimer's Disease. Using a mouse model, researchers found increased p38 activation in microglia of the hippocampus during aging. Interestingly, these mice also displayed activated rod microglia, although p38 activation was decreased in this subpopulation. This suggests that rod microglia may have a neuroprotective phenotype in the context of tau pathology.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Leticia Perez-Sisques, Julia Solana-Balaguer, Genis Campoy-Campos, Nuria Martin-Flores, Anna Sancho-Balsells, Marcel Vives-Isern, Ferran Soler-Palazon, Marta Garcia-Forn, Merce Masana, Jordi Alberch, Esther Perez-Navarro, Albert Giralt, Cristina Malagelada
Summary: RTP801 is increased in neurodegenerative diseases and its downregulation can improve behavioral abnormalities. This study found that RTP801 levels are increased in the hippocampus of HD patients, correlated with gliosis markers. Silencing RTP801 in the dorsal hippocampus of HD mouse models improved cognitive alterations and reduced inflammation.
Article
Neurosciences
Veronica Brito, Enrica Montalban, Anna Sancho-Balsells, Anika Pupak, Francesca Flotta, Merce Masana, Silvia Gines, Jordi Alberch, Claire Martin, Jean-Antoine Girault, Albert Giralt
Summary: Motor skills learning is associated with cerebral and cerebellar cortices, basal ganglia nuclei, and now also found to involve the hippocampus. Transcriptional changes and reduced activity of pyramidal neurons in the CA1 region of the hippocampus are observed in mice trained in the accelerating rotarod. A subpopulation of Egr1-expressing pyramidal neurons in CA1 is activated during short-term and long-term training in the rotarod task. Manipulations of Egr1 or these neuronal ensembles affect motor learning performance, showing the importance of the hippocampus in controlling motor skill learning.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Neurosciences
Alvaro Sebastian-Serrano, Jesus Merchan-Rubira, Caternia Di Lauro, Carolina Bianchi, Lucia Soria-Tobar, Sonoko L. Narisawa, Jose L. Millan, Jesus Avila, Felix Hernandez, Miguel Diaz-Hernandez
Summary: This study demonstrates that increased activity of tissue-nonspecific alkaline phosphatase (TNAP) is critical for Tau-induced neurotoxicity. Upregulation of TNAP leads to intracellular Tau hyperphosphorylation and aggregation in neighboring cells, while genetic disruption of TNAP reduces the dephosphorylation of extracellular Tau, decreasing neuronal hyperactivity, brain atrophy, and hippocampal neuronal death. These findings suggest that TNAP blockade may be a novel and efficient therapy for tauopathies.
NEUROBIOLOGY OF DISEASE
(2022)
Review
Neurosciences
Felix Hernandez, Isidro Ferrer, Mar Perez, Juan Carlos Zabala, Jose Antonio del Rio, Jesus Avila
Summary: This article reexamines the aggregation of tau protein at primary, secondary, tertiary, and quaternary structures. Additionally, the presence of non-aggregated tau protein, which has been recently discovered, is also discussed.
Article
Neurosciences
Dahyun Yu, Nicole Zarate, Angel White, De'jah Coates, Wei Tsai, Carmen Nanclares, Francesco Cuccu, Johnny S. Yue, Taylor G. Brown, Rachel H. Mansky, Kevin Jiang, Hyuck Kim, Tessa Nichols-Meade, Sarah N. Larson, Katherine Gundry, Ying Zhang, Cristina Tomas-Zapico, Jose J. Lucas, Michael Benneyworth, Gulin Oz, Marija Cvetanovic, Alfonso Araque, Rocio Gomez-Pastor
Summary: This study investigated the role of protein kinase CK2 alpha' in the regulation of neuroinflammation and synaptic function in Huntington's disease. The results showed that CK2 alpha' haploinsufficiency can decrease pro-inflammatory cytokines, improve synaptic activity, and enhance motor coordination in a mouse model of Huntington's disease. These findings provide important clues for developing effective therapeutic strategies for Huntington's disease.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2022)
Article
Clinical Neurology
Alicia Garrido, Leticia Perez-Sisques, Cristina Simonet, Genis Campoy-Campos, Julia Solana-Balaguer, Nuria Martin-Flores, Manel Fernandez, Marta Soto, Donina Obiang, Ana Camara, Francesc Valldeoriola, Esteban Munoz, Yaroslau Compta, Esther Perez-Navarro, Jordi Alberch, Eduardo Tolosa, Maria-Jose Marti, Mario Ezquerra, Cristina Malagelada, Ruben Fernandez-Santiago
Summary: The purpose of this study was to investigate whether differential phosphorylation states of blood markers can identify patients with LRRK2 Parkinson's disease (PD). It was found that there were specific increases of P-Ser-473-AKT levels in all G2019S carriers, either L2PD or L2NMC, absent in iPD.
ANNALS OF NEUROLOGY
(2022)
Article
Clinical Neurology
Rocio Alfaro-Ruiz, Carolina Aguado, Alejandro Martin-Belmonte, Ana Esther Moreno-Martinez, Jesus Merchan-Rubira, Felix Hernandez, Jesus Avila, Yugo Fukazawa, Rafael Lujan
Summary: N-methyl-D-aspartate receptors are important in Alzheimer's disease, and their expression and localization differ at synaptic and extrasynaptic sites, which is associated with accumulation of phospho-tau.
Article
Biochemistry & Molecular Biology
Rocio Alfaro-Ruiz, Carolina Aguado, Alejandro Martin-Belmonte, Ana Esther Moreno-Martinez, Jesus Merchan-Rubira, Felix Hernandez, Jesus Avila, Yugo Fukazawa, Rafael Lujan
Summary: The accumulation of tau proteins in diseases like Alzheimer's disease is associated with alterations in glutamate receptor dynamics, leading to synaptic dysfunction. This study investigated the impact of tau pathology on AMPAR expression, density, and distribution in the hippocampus of P301S mice. The results showed that the accumulation of phospho-tau resulted in reduced AMPAR density in excitatory synapses on pyramidal cell spines and interneuron dendrites, as well as at extrasynaptic sites in CA1 pyramidal cells and interneurons. These findings suggest that tau pathology disrupts AMPAR trafficking and synaptic transmission, contributing to the pathological events in Alzheimer's disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Ivana Olla, Antonio F. Pardinas, Alberto Parras, Ivo H. Hernandez, Maria Santos-Galindo, Sara Pico, Luis F. Callado, Ainara Elorza, Claudia Rodriguez-Lopez, Gonzalo Fernandez-Miranda, Eulalia Belloc, James T. R. Walters, Michael C. O'Donovan, Raul Mendez, Claudio Toma, J. Javier Meana, Michael J. Owen, Jose J. Lucas
Summary: Aberrant splicing of the CPEB4 gene leads to misexpression of schizophrenia risk genes, providing a novel etiological mechanism for schizophrenia.
BIOLOGICAL PSYCHIATRY
(2023)
Letter
Oncology
Marta Garcia-Forn, Carla Castany-Pladevall, Arantxa Golbano, Jesus Perez-Perez, Veronica Brito, Jaime Kulisevsky, Esther Perez-Navarro
CLINICAL AND TRANSLATIONAL MEDICINE
(2023)
Meeting Abstract
Clinical Neurology
Marc Espina, Laura Lopez-Molina, Anika Pupak, Nadia Di Franco, Veronica Brito, Juan Carlos Arevalo, Silvia Gines
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Meeting Abstract
Clinical Neurology
Anika Pupak, Irene Rodriguez-Navarro, Ankita Singh, Ulf Vang Orom, Jordi Alberch, Silvia Gines, Veronica Brito
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)