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Effects of P301L-TAU on post-translational modifications of microtubules in human iPSC-derived cortical neurons and TAU transgenic mice

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Neural Regeneration research 2025年第8期20卷 2348-2360页

作者： Mohamed Aghyad Al Kabbani Christoph Köhler Hans Zempel Institute of Human Genetics Faculty of Medicine and University Hospital CologneUniversity of CologneCologneGermany center for molecular medicine Cologne(CMMC) University of CologneCologneGermany center Anatomy Department ⅡMedical FacultyUniversity of CologneCologneGermany

TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the *** is missorted and aggregated in an array of diseases known as *** are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing *** impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule *** therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to *** investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic *** sum,P301L-TAU results in changes in micr

关键词： human induced pluripotent stem cell microtubules P301L pR5 mice TAU tauopathy tubulin code

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Amyloid-β-induced disruption of axon-initial-segment mitochondria localization:consequences for TAU missorting in Alzheimer's disease pathology

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Neural Regeneration research 2025年第5期20卷 1407-1408页

作者： Daniel Adam Felix Langerscheidt Hans Zempel Institute of Human Genetics University Hospital CologneCologneGermany center for molecular medicine Cologne(CMMC) University of CologneCologneGermany

TAU is a neuronal microtubule-associated protein preferentially located in *** a battery of neurodegenerative diseases termed"tauopathies,"including Alzheimer's disease (AD),TAU is missorted and abnormally phosphorylated,leading to filamentous accumulations of hyperphosphorylated TAU,a pathological hallmark and potential disease driver of AD and related tauopathies (Zempel,2024).

关键词： Alzheimer tau diseases

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Phosphodiesterase 9 localization in cytoplasm and nucleus:the gateway to selective targeting in neuroprotection?

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Neural Regeneration research 2025年第6期20卷 1701-1702页

作者： Giovanni Ribaudo Matteo Giannangeli Margrate Anyanwu Alessandra Gianoncelli Department of molecular and Translational medicine University of BresciaBresciaItaly

The umbrella term"neurodege ne rative disorders"(NDDs) refers to several conditions characterized by a progressive loss of structure and function of cells belonging to the nervous *** diseases affect more than 50million people *** disorders are characterized by sundry factors and pathophysiological mechanisms that a re challenging to be fully *** of these rely on cell signaling pathways to preserve homeostasis,involving second messengers such as cyclic adenosine monophosphate (cAMP)and cyclic guanosine 3',5'-monophosphate(cGMP).Their ability to control the duration and amplitude of the signaling cascade is given by the presence of several common and uncommon *** kinases A and G (PKA and PKG),phosphodiesterases (PDEs),and scaffold proteins are among them.

关键词： gateway homeostasis preserve

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Proteostasis failure:at the intersection between aging and Alzheimer's disease

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Neural Regeneration research 2025年第11期20卷 3221-3222页

作者： Natalia Poblete Claudio Hetz center for Geroscience Brain Health and MetabolismSantiagoChile Biomedical Neuroscience Institute Faculty of MedicineUniversity of ChileSantiagoChile Program of Cellular and molecular Biology Institute of Biomedical SciencesFaculty of MedicineUniversity of ChileSantiagoChile Buck Institute for research on Aging NovatoCAUSA

Lifestyle and demographics of the world's population are causing serious health problems impacting the brain,increasing the incidence of Alzheimer's disease(AD)and other types of *** we have gained important insights into the pathogenic mechanisms of AD,only palliative care is available to *** is characterized by the abnormal deposition of protein aggregates in the brain formed by amyloid β and hyper-phosphorylated,Tau in addition to neuroinflammation.

关键词： Alzheimer amyloid stasis

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NECAB family of neuronal calcium-binding proteins in health and disease

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Neural Regeneration research 2025年第5期20卷 1236-1243页

作者： Diones Bueno Michael K.E.Schafer Sudena Wang Michael J.Schmeisser Axel Methner Institute for molecular medicine University Medical Center of the Johannes Gutenberg-UniversityMainzGermany Department of Anesthesiology University Medical Center of the Johannes Gutenberg-UniversityMainzGermany Institute of Anatomy University Medical Center of the Johannes Gutenberg-UniversityMainzGermany

The N-terminal EF-hand calcium-binding proteins 1–3(NECAB1–3) constitute a family of predominantly neuronal proteins characterized by the presence of at least one EF-hand calcium-binding domain and a functionally less well characterized C-terminal antibiotic biosynthesis monooxygenase domain. All three family members were initially discovered due to their interactions with other proteins. NECAB1 associates with synaptotagmin-1, a critical neuronal protein involved in membrane trafficking and synaptic vesicle exocytosis. NECAB2 interacts with predominantly striatal G-protein-coupled receptors, while NECAB3 partners with amyloid-β A4 precursor protein-binding family A members 2 and 3, key regulators of amyloid-β production. This demonstrates the capacity of the family for interactions with various classes of proteins. NECAB proteins exhibit distinct subcellular localizations: NECAB1 is found in the nucleus and cytosol, NECAB2 resides in endosomes and the plasma membrane, and NECAB3 is present in the endoplasmic reticulum and Golgi apparatus. The antibiotic biosynthesis monooxygenase domain, an evolutionarily ancient component, is akin to atypical heme oxygenases in prokaryotes but is not wellcharacterized in vertebrates. Prokaryotic antibiotic biosynthesis monooxygenase domains typically form dimers, suggesting that calcium-mediated conformational changes in NECAB proteins may induce antibiotic biosynthesis monooxygenase domain dimerization, potentially activating some enzymatic properties. However, the substrate for this enzymatic activity remains uncertain. Alternatively, calcium-mediated conformational changes might influence protein interactions or the subcellular localization of NECAB proteins by controlling the availability of protein–protein interaction domains situated between the EF hands and the antibiotic biosynthesis monooxygenase domain. This review summarizes what is known about genomic organization, tissue expression, intracellular localization, interac

关键词： calcium EF hand mitochondria nervous system signal transduction

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Generation of brain vascular heterogeneity:recent advances from the perspective of angiogenesis

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Neural Regeneration research 2025年第7期20卷 2013-2014页

作者： Nathanael J.Lee Ryota L.Matsuoka Department of Neurosciences Lerner Research InstituteCleveland ClinicClevelandOHUSA Department of molecular medicine Cleveland Clinic Lerner College of MedicineCase Western Reserve UniversityClevelandOHUSA

Heterogeneous proper t i es of vascular endothelial cells in the brain:The brain displays large energy dynamics and consumption,and this high level of metabolic demands is fulfilled by a continuous supply of glucose and oxygen through its vascular *** vasculature consists of highly divergent blood vessel branches,giving rise to a dense network of capillaries that supply blood to all cells across the *** elaborated vascular network is thought to develop via angiogenesis,a process in which new blood vessels grow from pre-existing *** capillaries exhibit organotypic features distinct from other tissues and are formed primarily by two major endothelial cell(EC)types:those that form the semi-permeable blood-brain barrier(BBB)and those that develop highly permeable pores known as fenestrae(Matsuoka et al.,2022).The structural and functional differences between BBB and fenestrated vascular ECs represent a fundamental feature of brain vasculature and form the foundation for both brain function and homeostasis.

关键词： angiogenesis homeostasis network

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Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

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Neural Regeneration research 2025年第11期20卷 3113-3123页

作者： Theodora Ntetsika Sergiu-Bogdan Catrina Ioanna Markaki Department of Clinical Neuroscience Karolinska InstituteStockholmSweden Department of Neurology Karolinska University HospitalStockholmSweden Department of molecular medicine and Surgery Karolinska InstituteStockholmSweden center for Diabetes Academic Specialist CenterStockholmSweden center for Neurology Academic Specialist CenterStockholmSweden

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic *** data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular *** insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological *** contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

关键词： brain insulin resistance brain insulin signaling diabetes type 2 GLP-1 receptor agonists GLP-1 signaling insulin resistance insulin signaling neurodegeneration Parkinson's disease targeted therapy

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Emerging potential of progranulin-dependent SorCS2 signaling in healthy and diseased nervous systems

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Neural Regeneration research 2025年第9期20卷 2591-2593页

作者： Alena Salasova Anders Nykjær Danish research Institute of Translational Neuroscience DANDRITE-Nordic EMBL Partnership for molecular medicine and Centre of Excellence PROMEMODepartment of BiomedicineAarhus UniversityAarhusDenmark

The formation of the mammalian nervous system and its maturation into sensory,motor,cognitive,and behavioral circuits is a complex process that begins during early embryogenesis and lasts until young *** neurodevelopm... 详细信息

关键词： progr jointly CS2

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Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA center for molecular Innovation and Drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

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The Citron homology domain of MAP4Ks improves outcomes of traumatic brain injury

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Neural Regeneration research 2025年第11期20卷 3233-3244页

作者： Xiaoling Zhong Wenjiao Tai Meng-Lu Liu Shuaipeng Ma Tianjin Shen Yuhua Zou Chun-Li Zhang Department of molecular Biology University of Texas Southwestern Medical CenterDallasTXUSA Hamon center for Regenerative Science and medicine University of Texas Southwestern Medical CenterDallasTXUSA Peter O’Donnell Jr.Brain Institute University of Texas Southwestern Medical CenterDallasTXUSA

The mitogen-activated protein kinase kinase kinase kinases(MAP4Ks)signaling pathway plays a pivotal role in axonal regrowth and neuronal degeneration following *** targeting this pathway is beneficial to brain injury remains *** this study,we showed that adeno-associated virus-delivery of the Citron homology domain of MAP4Ks effectively reduces traumatic brain injury-induced reactive gliosis,tauopathy,lesion size,and behavioral *** inhibition of MAP4Ks replicated the ameliorative effects observed with expression of the Citron homology ***,the Citron homology domain acted as a dominant-negative mutant,impeding MAP4K-mediated phosphorylation of the dishevelled proteins and thereby controlling the Wnt/β-catenin *** findings implicate a therapeutic potential of targeting MAP4Ks to alleviate the detrimental effects of traumatic brain injury.

关键词： adeno-associated virus Citron homology Citron homology domain gene therapy mitogen-activated protein kinase kinase kinase kinases traumatic brain injury

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