Neural Regeneration Research最新文献

{"title":"The Cullin3-Ring E3 ubiquitin ligase complex and USP14 regulate spastin-mediated microtubule severing and promotion of neurite outgrowth.","authors":"Zhenbin Cai, Hui Wu, Tao Jiang, Ao Ma, Zhichao Meng, Jiehao Zhu, Hongsheng Lin, Yaozhong Liang, Guowei Zhang, Minghui Tan","doi":"10.4103/NRR.NRR-D-25-00037","DOIUrl":"https://doi.org/10.4103/NRR.NRR-D-25-00037","url":null,"abstract":"<p><p>JOURNAL/nrgr/04.03/01300535-202604000-00044/figure1/v/2025-06-30T060627Z/r/image-tiff Post-translational modification of spastin enables precise spatiotemporal control of its microtubule severing activity. However, the detailed mechanism by which spastin turnover is regulated in the context of neurite outgrowth remains unknown. Here, we found that spastin interacted with ubiquitin and was significantly degraded by K48-mediated poly-ubiquitination. Cullin3 facilitated spastin degradation and ubiquitination. RING-box protein 1, but not RING-box protein 2, acted synergistically with Cullin3 protein to regulate spastin degradation. Overexpression of Culin3 or BRX1 markedly suppressed spastin expression, and inhibited spastin-mediated microtubule severing and promotion of neurite outgrowth. Moreover, USP14 interacted directly with spastin to mediate its de-ubiquitination. USP14 overexpression significantly increased spastin expression and suppressed its ubiquitination and degradation. Although co-expression of spastin and USP14 did not enhance microtubule severing, it did increase neurite length in hippocampal neurons. Taken together, these findings elucidate the intricate regulatory mechanisms of spastin turnover, highlighting the roles of the Cullin-3-Ring E3 ubiquitin ligase complex and USP14 in orchestrating its ubiquitination and degradation. The dynamic interplay between these factors governs spastin stability and function, ultimately influencing microtubule dynamics and neuronal morphology. These insights shed light on potential therapeutic targets for neurodegenerative disorders associated with spastin defects.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":"21 4","pages":"1641-1651"},"PeriodicalIF":5.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pericyte-glial cell interactions: Insights into brain health and disease.","authors":"Ali Sepehrinezhad, Ali Gorji","doi":"10.4103/NRR.NRR-D-24-01472","DOIUrl":"10.4103/NRR.NRR-D-24-01472","url":null,"abstract":"<p><p>Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, maturation, and maintenance of the central nervous system. An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes, microglia, and astrocytes. These communications govern numerous critical brain processes, including angiogenesis, neurovascular unit homeostasis, blood-brain barrier integrity, cerebral blood flow regulation, and immune response initiation. Glial cells and pericytes participate in dynamic and reciprocal interactions, with each influencing and adjusting the functionality of the other. Pericytes have the ability to control astrocyte polarization, trigger differentiation of oligodendrocyte precursor cells, and initiate immunological responses in microglia. Various neurological disorders that compromise the integrity of the blood-brain barrier can disrupt these communications, impair waste clearance, and hinder cerebral blood circulation, contributing to neuroinflammation. In the context of neurodegeneration, these disruptions exacerbate pathological processes, such as neuronal damage, synaptic dysfunction, and impaired tissue repair. This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system. It highlights their essential roles in neurovascular function and disease progression, providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"1253-1263"},"PeriodicalIF":5.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Injury-induced KIF4A neural expression and its role in Schwann cell proliferation suggest a dual function for this kinesin in neural regeneration.","authors":"Patrícia D Correia, Bárbara M de Sousa, Jesús Chato-Astrain, Joana Paes de Faria, Veronica Estrada, João B Relvas, Hans W Müller, Víctor Carriel, Frank Bosse, Sandra I Vieira","doi":"10.4103/NRR.NRR-D-24-00232","DOIUrl":"10.4103/NRR.NRR-D-24-00232","url":null,"abstract":"<p><p>JOURNAL/nrgr/04.03/01300535-202604000-00041/figure1/v/2025-06-30T060627Z/r/image-tiff Contrary to the adult central nervous system, the peripheral nervous system has an intrinsic ability to regenerate that relies on the expression of regeneration-associated genes, such as some kinesin family members. Kinesins contribute to nerve regeneration through the transport of specific cargo, such as proteins and membrane components, from the cell body towards the axon periphery. We show here that KIF4A, associated with neurodevelopmental disorders and previously believed to be only expressed during development, is also expressed in the adult vertebrate nervous system and up-regulated in injured peripheral nervous system cells. KIF4A is detected both in the cell bodies and regrowing axons of injured neurons, consistent with its function as an axonal transporter of cargoes such as β1-integrin and L1CAM. Our study further demonstrates that KIF4A levels are greatly increased in Schwann cells from injured distal nerve stumps, particularly at a time when they are reprogrammed into an essential proliferative repair phenotype. Moreover, Kif4a mRNA levels were approximately ~ 6-fold higher in proliferative cultured Schwann cells compared with non-proliferative ones. A hypothesized function for Kif4a in Schwann cell proliferation was further confirmed by Kif4a knockdown, as this significantly reduced Schwann cell proliferation in vitro . Our findings show that KIF4A is expressed in adult vertebrate nervous systems and is up-regulated following peripheral injury. The timing of KIF4A up-regulation, its location during regeneration, and its proliferative role, all suggest a dual role for this protein in neuroregeneration that is worth exploring in the future.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"1607-1620"},"PeriodicalIF":5.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Damage and repair in retinal degenerative diseases: Molecular basis through clinical translation.","authors":"Ziting Zhang, Junfeng Ma, Wahid Shah, Xin Quan, Tao Ding, Yuan Gao","doi":"10.4103/NRR.NRR-D-24-01016","DOIUrl":"10.4103/NRR.NRR-D-24-01016","url":null,"abstract":"<p><p>Retinal ganglion cells are the bridging neurons between the eye and the central nervous system, transmitting visual signals to the brain. The injury and loss of retinal ganglion cells are the primary pathological changes in several retinal degenerative diseases, including glaucoma, ischemic optic neuropathy, diabetic neuropathy, and optic neuritis. In mammals, injured retinal ganglion cells lack regenerative capacity and undergo apoptotic cell death within a few days of injury. Additionally, these cells exhibit limited regenerative ability, ultimately contributing to vision impairment and potentially leading to blindness. Currently, the only effective clinical treatment for glaucoma is to prevent vision loss by lowering intraocular pressure through medications or surgery; however, this approach cannot halt the effect of retinal ganglion cell loss on visual function. This review comprehensively investigates the mechanisms underlying retinal ganglion cell degeneration in retinal degenerative diseases and further explores the current status and potential of cell replacement therapy for regenerating retinal ganglion cells. As our understanding of the complex processes involved in retinal ganglion cell degeneration deepens, we can explore new treatment strategies, such as cell transplantation, which may offer more effective ways to mitigate the effect of retinal degenerative diseases on vision.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"1383-1395"},"PeriodicalIF":5.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"mTORC1 and mTORC2 synergy in human neural development, disease, and regeneration.","authors":"Navroop K Dhaliwal, Julien Muffat, Yun Li","doi":"10.4103/NRR.NRR-D-24-00961","DOIUrl":"10.4103/NRR.NRR-D-24-00961","url":null,"abstract":"","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"1552-1553"},"PeriodicalIF":5.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organelle symphony: Nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in stroke pathobiology.","authors":"Ziliang Hu, Mingyue Zhao, Hangyu Shen, Liangzhe Wei, Jie Sun, Xiang Gao, Yi Huang","doi":"10.4103/NRR.NRR-D-24-01404","DOIUrl":"10.4103/NRR.NRR-D-24-01404","url":null,"abstract":"<p><p>Strokes include both ischemic stroke, which is mediated by a blockade or reduction in the blood supply to the brain, and hemorrhagic stroke, which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain. Stroke is a life-threatening cerebrovascular condition characterized by intricate pathophysiological mechanisms, including oxidative stress, inflammation, mitochondrial dysfunction, and neuronal injury. Critical transcription factors, such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B, play central roles in the progression of stroke. Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage, inflammatory responses, and cytotoxic agents. It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function, endoplasmic reticulum stress, and lysosomal activity and regulating metabolic pathways and cytokine expression. Conversely, nuclear factor-kappaB is closely associated with mitochondrial dysfunction, the generation of reactive oxygen species, oxidative stress exacerbation, and inflammation. Nuclear factor-kappaB contributes to neuronal injury, apoptosis, and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators. The interplay between these pathways, potentially involving crosstalk among various organelles, significantly influences stroke pathophysiology. Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted, individualized, cell type-specific treatments. In this review, we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke, with an emphasis on their roles in oxidative stress, inflammation, and neuroprotection.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"1483-1496"},"PeriodicalIF":5.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.","authors":"Min Zhou, Min Zheng, Siyao Liang, Maomao Li, Jiarui Ma, Shiyu Zhang, Xinyao Song, Yonglin Hu, Yuhong Lyu, Xingkun Ou, Changwu Yue","doi":"10.4103/NRR.NRR-D-24-01507","DOIUrl":"10.4103/NRR.NRR-D-24-01507","url":null,"abstract":"<p><p>The cure rate for chronic neurodegenerative diseases remains low, creating an urgent need for improved intervention methods. Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases. This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases, aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options. We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy, inhibiting mitochondrial fission, enhancing mitochondrial biogenesis, applying mitochondria-targeting antioxidants, and transplanting mitochondria. Each method has unique advantages and potential limitations, making them suitable for various therapeutic situations. Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression, especially in the early stages. In contrast, those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism. Mitochondrial transplantation, while still experimental, holds great promise for restoring the function of damaged cells. Future research should focus on exploring the mechanisms and effects of these intervention strategies, particularly regarding their safety and efficacy in clinical settings. Additionally, the development of innovative mitochondria-targeting approaches, such as gene editing and nanotechnology, may provide new solutions for treating chronic neurodegenerative diseases. Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"1409-1427"},"PeriodicalIF":5.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial damage-associated molecular patterns: Neuroimmunomodulators in central nervous system pathophysiology.","authors":"Noah A H Brooks, Ishvin Riar, Andis Klegeris","doi":"10.4103/NRR.NRR-D-24-01459","DOIUrl":"10.4103/NRR.NRR-D-24-01459","url":null,"abstract":"<p><p>Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. It is driven by non-neuronal glial cells, mainly microglia and astrocytes. Microglia are the resident immune cells of the central nervous system, while astrocytes are the main support cells for neuronal functions but can also participate in neuroimmune responses. Both these glial cell types can become reactive upon detection of certain endogenous intracellular molecules that appear in the extracellular space under specific circumstances; these can be pathology-associated abnormal structures, such as amyloid β proteins, or damage-associated molecular patterns released from injured cells, including their mitochondria. Once in the extracellular space, damage-associated molecular patterns act as ligands for specific pattern recognition receptors expressed by glia inducing their reactivity and neuroimmune responses. This review considers the following mitochondrial damage-associated molecular patterns: heme, cytochrome c, cardiolipin, adenosine triphosphate, mitochondrial DNA, mitochondrial transcription factor A, N-formyl peptides, and the tricarboxylic acid cycle metabolites: succinate, fumarate, and itaconate. We describe their well-established functions as damage-associated molecular patterns of the peripheral tissues before summarizing available evidence indicating these molecules may also play significant roles in the neuroimmune processes of the central nervous system. We highlight the pattern recognition receptors that mitochondrial damage-associated molecular patterns interact with and the cellular signaling mechanisms they modulate. Our review demonstrates that some mitochondrial damage-associated molecular patterns, such as cytochrome c, adenosine triphosphate, and mitochondrial transcription factor A, have already demonstrated significant effects on the central nervous system. In contrast, others including cardiolipin, mitochondrial DNA, N-formyl peptides, succinate, fumarate, and itaconate, will require additional studies corroborating their roles as damage-associated molecular patterns in the central nervous system. For all of the reviewed mitochondrial damage-associated molecular patterns, there is a shortage of studies using human cells and tissues, which is identified as a significant knowledge gap. We also assess the need for targeted research on the effects of mitochondrial damage-associated molecular patterns in the central nervous system pathologies where their roles are understudied. Such studies could identify novel treatment strategies for multiple neurodegenerative diseases, which are characterized by chronic neuroinflammation and currently lack effective therapies.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"1322-1338"},"PeriodicalIF":5.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell therapy rejuvenates the neuro-glial-vascular unit.","authors":"Bandy Chen","doi":"10.4103/NRR.NRR-D-24-01359","DOIUrl":"https://doi.org/10.4103/NRR.NRR-D-24-01359","url":null,"abstract":"","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":"21 4","pages":"1542-1543"},"PeriodicalIF":5.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropsychiatric symptoms and apolipoprotein E genotypes in neurocognitive disorders.","authors":"Madia Lozupone, Ivana Leccisotti, Anita Mollica, Giuseppe Berardino, Maria Claudia Moretti, Mario Altamura, Antonello Bellomo, Antonio Daniele, Vittorio Dibello, Vincenzo Solfrizzi, Emanuela Resta, Francesco Panza","doi":"10.4103/NRR.NRR-D-24-01274","DOIUrl":"10.4103/NRR.NRR-D-24-01274","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E ( APOE ) genotypes and their corresponding protein (ApoE) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes ( APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among ApoE, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of ApoE's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides ApoE-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease (depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due ","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"1528-1541"},"PeriodicalIF":5.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}