Cellular and Molecular Neurobiology最新文献

{"title":"β-Hydroxybutyrate Maintains Energetically Demanding Neural Functions During Exogenous Glucose Deprivation.","authors":"Rachel L Ricks, Dallin S Nevers, Tyler Poulos, T Luke Shafer, Clayton Dunford, Jason M Hansen, Paul R Reynolds, Benjamin T Bikman, R Ryley Parrish","doi":"10.1007/s10571-026-01834-3","DOIUrl":"https://doi.org/10.1007/s10571-026-01834-3","url":null,"abstract":"<p><p>Ketone bodies are a major source of cerebral energy during fasting and the ketogenic diet, but whether they can sustain brain tissue metabolism when glucose is absent remains uncertain. This question is difficult to resolve in vivo because circulating glucose is maintained, even during starvation, through endogenous production. We therefore used an ex vivo brain preparation to examine the metabolic capacity of tissue following incubation with β-hydroxybutyrate (BHB) as the only exogenous fuel, isolating brain tissue from its primary endogenous glucose sources. Mitochondrial respiration was monitored following 4-hour incubation in glucose-free, BHB-rich artificial cerebrospinal fluid, and tissue resilience was tested by inducing spreading depolarization, a severe energetic challenge that requires rapid restoration of ionic and metabolic homeostasis. Following acute reliance on exogenous BHB, in addition to endogenous energy reserves, mitochondrial electron transfer system function persisted, with lower O₂ flux than following incubation with exogenous glucose. BHB-supported tissue maintained sufficient energetic capacity to generate and recover from repeated spreading depolarizations. In contrast, tissue relying solely on endogenous energy reserves failed to undergo repeated spreading depolarizations, suggesting that exogenous BHB provided the needed short-term energetic support beyond that available from endogenous substrates in the complete absence of exogenous glucose. The results broaden our understanding of cerebral fuel flexibility and provide evidence that BHB can support highly energetic neural function in the absence of exogenous glucose.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using Brain Organoids to Explore Human Neurobiology.","authors":"Hany E Marei, Anwarul Hasan","doi":"10.1007/s10571-026-01808-5","DOIUrl":"10.1007/s10571-026-01808-5","url":null,"abstract":"<p><p>One of the major challenges in neuroscience is understanding how the human brain develops into a highly organized and functionally integrated organ, because many developmental processes cannot be investigated directly in humans and are not fully recapitulated in animal models. Brain organoids derived from human pluripotent stem cells have emerged as powerful three-dimensional (3D) experimental models that recapitulate key features of human neurodevelopment, including regional patterning, cellular diversification, and neural circuit assembly. Recent advances in long-term organoid culture, organoid bioengineering, vascularization, assembloid technology, transplantation, multi-omics, and artificial intelligence have substantially expanded the applications of brain organoids to investigate human neurodevelopment, model neurological disorders, support drug discovery, and advance therapeutic development. Integration of single-cell and spatial multi-omics with computational approaches has enabled robust molecular benchmarking, assessment of developmental fidelity, and evaluation of organoid reproducibility, facilitating direct comparison with primary human fetal brain tissue. However, current organoid systems remain limited owing to incomplete cellular and tissue complexity, inter-organoid variability, limited vascularization, limited functional maturation, and incomplete physiological integration. Continued advances in tissue engineering, computational biology, and standardized differentiation protocols are expected to enhance the biological fidelity and translational utility of brain organoids for basic and translational neuroscience, as well as mechanistic and translational research.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Prioritization of Plasma Proteins Across Dementia Subtypes: A Proteome-Wide Mendelian Randomization and Bayesian Colocalization Analysis.","authors":"Xinyang Yan, Longxiao Zhang, Jiaxi Li, Jinning Song","doi":"10.1007/s10571-026-01819-2","DOIUrl":"10.1007/s10571-026-01819-2","url":null,"abstract":"<p><p>Dementia is clinically and biologically heterogeneous, and genetically supported plasma protein associations across dementia subtypes remain incompletely characterized. We aimed to genetically prioritize plasma proteins associated with overall dementia and major dementia subtypes using proteome-wide Mendelian randomization (MR) and Bayesian colocalization. We used the UK Biobank Pharma Proteomics Project (UKB-PPP) as a harmonized source of cis-protein quantitative trait loci (cis-pQTLs) for 2,941 Olink-measured plasma analytes. The European-ancestry discovery cis-pQTL analysis included up to 34,557 participants, whereas 54,219 participants were profiled in the overall UKB-PPP. Outcomes included FinnGen R10 genome-wide association studies (GWAS) for dementia, Alzheimer's dementia, vascular dementia, frontotemporal dementia, and unspecified dementia, plus a European GWAS for dementia with Lewy bodies. At the nominal threshold of P < 0.05, 134, 132, 102, 78, 101, and 112 exploratory protein-outcome signals were observed for dementia, Alzheimer's dementia, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and unspecified dementia, respectively; 23 associations remained significant after outcome-specific Benjamini-Hochberg false discovery rate (FDR) correction. Key FDR-significant proteins included APOE, NECTIN2, PVR, SERPINF2, GRN, TREM2, and ATXN2L. The strongest risk and protective associations were NECTIN2 with Alzheimer's dementia (odds ratio [OR] = 2.650, 95% confidence interval [CI]: 1.875-3.744, FDR-adjusted P = 1.58 × 10^- 5) and ATXN2L with dementia (OR = 0.408, 95% CI: 0.255-0.654, FDR-adjusted P = 0.0370), respectively. Strong colocalization support was observed for selected SERPINF2 and TREM2 associations. These findings genetically prioritize several plasma proteins as candidate biomarkers and potential therapeutic targets across dementia subtypes, but do not establish that circulating protein abundance directly mediates dementia risk.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Crossroads in Neurobiology: From Cellular Vulnerability to Therapeutic Opportunity.","authors":"Rita Valenzuela, Ana I Rodríguez-Pérez","doi":"10.1007/s10571-026-01822-7","DOIUrl":"10.1007/s10571-026-01822-7","url":null,"abstract":"<p><p>Mitochondria integrate metabolic, signalling, and quality-control pathways that are critical for neuronal and glial homeostasis. Beyond ATP production, they regulate redox balance, calcium dynamics, proteostasis, innate immune signalling, and the molecular pathways governing cell survival and death. This Closing Editorial synthesizes the main advances reported in this Collection across neurodegeneration, neurodevelopmental vulnerability, inherited mitochondrial disorders, neurotrauma, drug-induced neurotoxicity, and neuroimmune regulation. Collectively, these studies establish mitochondrial dysfunction as a heterogeneous and context-dependent process rather than a uniform or secondary consequence of neurological disease. Mitochondrial alterations are dynamically regulated across cell types, subcellular compartments, and disease stages, and are tightly coupled to inter-organelle communication and cellular stress-response pathways. The contributions highlight convergent mechanisms linking astrocytic mitochondrial DNA damage, dysregulated RNA-binding proteins, altered mitochondria-endoplasmic reticulum contacts, disrupted iron and redox homeostasis, and mitochondrial-inflammatory signalling to neuronal vulnerability and impaired circuit integrity. They also identify potential therapeutic targets while defining key unresolved questions, particularly the need to establish mechanistic causality, delineate cell- and compartment-specific mitochondrial responses, and validate findings using clinically relevant models and outcome measures. Overall, this Collection positions mitochondrial biology as a mechanistic framework connecting metabolic dysfunction, cellular stress, neuroinflammation, and neuronal degeneration, and supports its development as a therapeutic target for disease-modifying interventions in neurological disorders.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13546276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148896571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Converging pathomechanisms link SARS-CoV-2 infection with major neurodegenerative diseases.","authors":"Feng Q HeFeng, Andrea Martí-Sarrias, Heval Atas Guvenilir, Renata Baptista Vieira de Sá, Adithya Sridhar, Undine Haferkamp, Fatima El Kach-Marso, Sarah Bauermeister, Anett Hudák, Aristeidis Roubanis, Jochen Ohnmacht, Priya Sethumadhavan, Markus Ollert, Martin Hofmann-Apitius, Arcadi Navarro, Alpha Tom Kodamullil, Ole Pless, Tamas Letoha, Sandra Acosta, Rejko Krüger","doi":"10.1007/s10571-026-01785-9","DOIUrl":"10.1007/s10571-026-01785-9","url":null,"abstract":"<p><p>Neurological complications are among typical clinical manifestations, both during the acute phase of SARS-CoV-2 infection and long-term post-acute COVID-19 sequelae, i.e., Long COVID. A growing body of evidence connects SARS-CoV-2 infection to systemic inflammation, peripheral immune dysregulation, functional alteration of the blood-brain barrier (BBB), neuroinflammatory processes, mitochondrial dysfunction and pathological protein aggregation, all of which are central to the pathogenesis of major neurodegenerative diseases. In this review, we discuss the converging shared underlying molecular mechanisms that link the 'acute' SARS-CoV-2 infection that often only lasts for days and 'chronic' neurodegenerative diseases that often take decades to develop. We further review human induced pluripotent stem cells (iPSCs)-derived brain organoid and BBB models for Parkinson's disease (PD) and Alzheimer's disease (AD) as well as artificial intelligence (AI)-facilitated knowledge graph methods that are used to hypothesize and validate the potential mechanistic links. We propose that besides the established links between viral infections and neurodegenerative or neuroinflammatory conditions, such as Epstein-Barr virus (EBV) in multiple sclerosis or herpes zoster in AD, SARS-CoV-2 infection might be another important factor driving the future burden of the most common neurodegenerative diseases.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13740441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149341034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noncanonical Signaling Network of Nogo-A: A New Perspective on Multi-target Regulation, Neuroplasticity, and Disease Intervention Beyond NgR.","authors":"Tao Yang, Yongxiang Yang, Jingmin Cheng, Kexia Fan, Yuan Ma, Dongbo Zou, Haifeng Shu, Sixun Yu","doi":"10.1007/s10571-026-01787-7","DOIUrl":"10.1007/s10571-026-01787-7","url":null,"abstract":"<p><p>The membrane protein Nogo-A, initially identified for its inhibitory role in axonal regeneration through the Nogo receptor (NgR), is now recognized as a central hub in a complex noncanonical signaling network. Recent evidence indicates that Nogo-A engages diverse receptors and intracellular pathways beyond NgR to modulate neuroplasticity, synaptic stability, and glial function. This multi-target regulatory capacity characterizes Nogo-A as a critical determinant of neural repair and degeneration, with implications for conditions such as spinal cord injury, multiple sclerosis, and Alzheimer's disease. Noncanonical Nogo-A signaling intersects with growth factor cascades, inflammatory responses, and cytoskeletal dynamics, offering novel therapeutic targets for neural repair. This review synthesizes current knowledge on alternative Nogo-A signaling mechanisms and highlights their potential to redefine strategies for neuroregeneration and disease intervention.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13737222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oligodendrocyte Lineage Dysfunction in Alzheimer's Disease: A Bidirectional, Stage-Dependent Account.","authors":"Xiaoxia Ning, Jiao Lan, Jifei Miao","doi":"10.1007/s10571-026-01792-w","DOIUrl":"10.1007/s10571-026-01792-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) has traditionally been framed as a neuronal disorder, yet white matter and myelin abnormalities are consistently detected in the preclinical period, before overt amyloid pathology or cognitive decline. This temporal relationship suggests that oligodendrocyte (OL) dysfunction acts upstream of, rather than downstream from, amyloid accumulation. In this review we argue that OL dysfunction and loss are a fundamental, mechanistically integrated component of AD pathogenesis, and we develop this argument as a single causal sequence. Central to it is the dual role of OLs in amyloid homeostasis: they express the complete amyloidogenic machinery and produce a quantitatively significant, comparatively aggregation-prone fraction of Aβ, while intact myelin is required for both axonal metabolic support and efficient Aβ clearance. A single lesion in the OL-myelin unit therefore simultaneously increases Aβ production and impairs its removal. We then examine why this lineage fails early: the exceptional metabolic and iron burden of myelin maintenance, combined with low glutathione reserves, renders OLs selectively vulnerable to oxidative injury and ferroptosis. This injury becomes self-sustaining through a metabolic-epigenetic feedback loop, diversion of finite microglial clearance toward myelin debris, and exhaustion of precursor-mediated repair, converting reversible injury into progressive myelin loss that further amplifies amyloid pathology. Together, these mechanisms define OL dysfunction as a self-reinforcing driver of AD and identify myelin preservation as a point of preventive leverage.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13737238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropathological Effects of Early Maternal Separation are Prevented by CORT113176, A Glucocorticoid Receptor Modulator.","authors":"M Niño Rodríguez, I J Esperante, L I Garay, H Hunt, E R De Kloet, M C Gonzalez Deniselle, A F De Nicola, M Meyer","doi":"10.1007/s10571-026-01789-5","DOIUrl":"10.1007/s10571-026-01789-5","url":null,"abstract":"<p><p>Early-life stress, such as maternal separation (MS), disrupts the pup´s hypothalamic-pituitary-adrenal (HPA) axis and causes neuropathological changes in several nervous system regions, including the spinal cord. This damage is driven by glucocorticoid receptor (GR) overactivation, which triggers neuroinflammation by dysfunctional changes in glial and neuronal cells. This study evaluated whether CORT113176 (dazucorilant)-a highly selective GR modulator- prevented the development of neuropathology in a murine model of repeated MS. Postnatal day 2 (PND2) NFR/NFR mice were assigned to three groups: control, MS (3-h daily maternal separation from PND2 to PND12 + vehicle), and MS + CORT113176 (30 mg/kg s.c. every other day). CORT113176 administration significantly mitigated the abnormalities effects of postnatal stress in the spinal cord. The selective GR modulator successfully: 1- decreased reactive astrogliosis and microglial activation markers (GFAP, GS, IBA1). 2- attenuated the expression of pro-inflammatory and stress-response genes. 3- protected neurons from stress-induced decreased BDNF and NeuN markers and 4- rescued myelin-producing cells and the water channel aquaporin-4 thus, pharmacological modulation of the GR with CORT113176 effectively intercepts the harmful neuroinflammatory and degenerative pathways triggered by early adverse experiences. These data provide robust evidence that selective GR inhibition is a viable therapeutic strategy against the pup's neurological consequences of maternal separation.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13737351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication.","authors":"Yuming Wu, Xue Zhang, Chenggang Gao, Zheng Zhang, Xuelian Liao, Yan Kang","doi":"10.1007/s10571-026-01786-8","DOIUrl":"10.1007/s10571-026-01786-8","url":null,"abstract":"<p><p>Neurodegenerative disorders involve a strong inflammatory component, yet the underlying inflammatory mechanisms may be heterogeneous across disease stage, cell type, and systemic context. A key unresolved question is how cellular and systemic stress is converted into sustained neuroinflammation. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate DNA-sensing hub that translates mislocalized self-DNA - derived from mitochondrial stress and mtDNA leakage, nuclear envelope instability, micronuclei formation, or impaired nucleic-acid disposal - into type I interferon, NF-kB, autophagy-related, and senescence-associated inflammatory programs. Rather than treating cGAS-STING as a universal disease-defining pathway, this review frames it as a context-dependent amplifier that becomes pathogenic when DNA-DAMP burden, defective mitochondrial quality control, neurovascular \"leakage\", and glial priming converge. We synthesize cell-type-specific evidence in microglia, astrocytes, neurons, and the neurovascular unit; compare mechanistic involvement across Alzheimer's disease, Parkinson's disease dementia and Lewy body disease, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), vascular and acute brain injury, and systemic inflammatory encephalopathies; and organize periphery-to-brain communication axes using an explicit evidence-grading framework. A distinctive contribution of this review is a two-hit model in which systemic inflammatory stressors and barrier dysfunction first lower cognitive resilience, followed by brain-resident mitochondrial/DNA damage programs that lock in complement-linked synaptopathy. We also evaluate pharmacological and lifestyle-based modulation, emphasizing biomarker-enriched trial design, CNS exposure, compartment-specific target engagement, and immune-safety constraints. This framework aims to clarify when, where, and in whom cGAS-STING modulation may preserve synapses and cognition without unacceptable immune trade-offs.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13710525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"At the Crossroads of Synapses and Signaling: The Role of LRRK2 in Neuronal Communication.","authors":"Angela Di Iacovo, Chiara D'Agostino, Giulia Casoli, Tiziana Romanazzi, Elena Bossi, Cristina Roseti","doi":"10.1007/s10571-026-01793-9","DOIUrl":"10.1007/s10571-026-01793-9","url":null,"abstract":"<p><p>Precise control of membrane protein localization and turnover is essential for synaptic function and circuit stability. Disruption of these processes alters the surface expression of receptors and transporters, ultimately impacting the excitatory/inhibitory (E/I) balance. Leucine-rich repeat kinase 2 (LRRK2) is emerging as a key regulator of these membrane-associated processes, acting at the interface between intracellular trafficking and synaptic signaling. LRRK2 integrates kinase activity with scaffolding functions to coordinate Rab-dependent vesicular trafficking, endosomal recycling, cytoskeletal dynamics, and endolysosomal pathways. Through these mechanisms, it controls the surface expression and distribution of synaptic receptors and neurotransmitter transporters in both neuronal and glial compartments. Pathogenic LRRK2 variants associated with Parkinson's disease (PD), converge on kinase hyperactivation and lead to sustained alterations in trafficking networks, resulting in selective mislocalization of membrane proteins. In this review, we examine how LRRK2-dependent trafficking mechanisms regulate key components of synaptic transmission, including glutamatergic and GABAergic receptors, as well as astrocytic transporters. We highlight how disruption of these processes affects neurotransmitter clearance, receptor activation, and ultimately E/I balance. Notably, accumulating evidence indicates that LRRK2 functions as an upstream coordinator of membrane organization at the crossroads of synaptic signaling and neurotransmitter homeostasis. Understanding how LRRK2 regulates trafficking pathways across cellular compartments provides mechanistic insight into circuit vulnerability in PD and highlights membrane-targeted strategies as potential approaches for restoring synaptic stability.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"46 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13710516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}