Molecular Neurodegeneration最新文献

{"title":"Parkinson's disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes.","authors":"Adamantios Mamais, Richard D Batchelor, Aravindraja Chairmandurai, Thomas B Ladd, Austin J Shute, Nitya Subrahmanian, Nunziata Maio, Christopher D Vulpe, Matthew J LaVoie","doi":"10.1186/s13024-026-00979-5","DOIUrl":"10.1186/s13024-026-00979-5","url":null,"abstract":"<p><strong>Background: </strong>Iron accumulation is a hallmark of sporadic and familial Parkinson's disease (PD) and correlates with clinical motor symptom severity. The biochemical mechanisms driving iron dyshomeostasis in PD brain and whether these are early or late events in the neurodegenerative process remain unknown. Nigral iron levels in LRRK2-PD patients have been reported to be even higher than in idiopathic PD, and greater in non-manifesting LRRK2 carriers than controls, suggesting that iron accumulation precedes clinical onset in LRRK2-associated PD. However, the cells affected and mechanisms governing iron dyshomeostasis in PD remain unclear.</p><p><strong>Methods: </strong>Here, we investigated multiple independent measures of iron homeostasis in human iPSCs and iPSC-derived models, including glutamatergic and dopaminergic neurons, and astrocytes, carrying pathogenic LRRK2 mutations. High-content and super-resolution microscopy of iron-specific probes and ICP-MS were used to determine iron content and distribution across different cell types and LRRK2 genotypes. Upstream effectors and downstream consequences of iron dyshomeostasis, including oxidative stress and ferroptosis-related phenotypes were also examined.</p><p><strong>Results: </strong>Pathogenic heterozygous LRRK2 mutations were associated with altered iron homeostasis across multiple human cell models. Lysosomal ferrous iron was consistently elevated across iPSC-derived glutamatergic neurons, dopaminergic neurons, and astrocytes carrying LRRK2 mutations and these phenotypes were reduced by varying degrees following treatment with the selective LRRK2 inhibitor, MLi-2. Importantly, we show that lipid peroxidation and ROS levels are elevated in isogenic LRRK2 mutant neurons, while iron chelation or MLi-2 reduced LRRK2-dependent ROS damage. In addition, CRISPR/Cas9-mediated loss of Rab8a produced overlapping iron-related phenotypes, while exogenous Rab8a expression normalized lysosomal iron levels in R1441C LRRK2 iPSCs, supporting a contributory role for Rab8a-dependent trafficking in these effects.</p><p><strong>Conclusions: </strong>Together, our findings show that pathogenic LRRK2 mutations converge on disrupted iron homeostasis across multiple human neural cell types, including dopaminergic neurons, and support a link between LRRK2 signaling, lysosomal iron dysregulation and ferroptosis-related stress.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"21 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AQP4-dependent enhancement of glymphatic function attenuates tau pathology and neurodegeneration in PS19 mice.","authors":"Kaoru Yamada,Kazuhisa Ishida,Asami Sakamoto,Hitoshi Shimada,Masaki Watanabe,Masato Shimojo,Hironaka Igarashi,Takeshi Iwatsubo","doi":"10.1186/s13024-026-00977-7","DOIUrl":"https://doi.org/10.1186/s13024-026-00977-7","url":null,"abstract":"BACKGROUNDThe glymphatic system facilitates cerebrospinal fluid-interstitial fluid exchange and contributes to the clearance of pathogenic proteins from the brain. Glymphatic dysfunction has been associated with Alzheimer's disease and related tauopathies; however, whether impaired glymphatic transport causally drives tau accumulation and neurodegeneration, and whether its enhancement confers therapeutic benefit, remains unclear.METHODSGlymphatic water dynamics in PS19 tau transgenic mice were assessed using JJVCPE, a novel MRI-based approach for evaluating brain water exchange. The effect of pharmacological activation of aquaporin-4 (AQP4) with TGN-073 on glymphatic cerebrospinal fluid influx was examined in wild-type mice using dynamic contrast-enhanced MRI. Tau pathology, neurodegeneration, and cerebrospinal fluid tau levels were analyzed in PS19 mice following chronic TGN-073 treatment. AQP4-deficient PS19 mice were examined to determine target specificity.RESULTSPS19 mice exhibited significant impairment of glymphatic water exchange at early disease stages, which progressively worsened with ageing. Pharmacological activation of AQP4 with TGN-073 robustly enhanced glymphatic-related tracer influx, reduced tau accumulation, neuronal loss, and gliosis, and was accompanied by increased cerebrospinal fluid tau levels. TGN-073 also restored perivascular AQP4 enrichment without significantly altering overall AQP4 abundance. Importantly, these beneficial effects were abolished in AQP4-deficient PS19 mice, demonstrating that both glymphatic enhancement and suppression of tau pathology and neurodegeneration are AQP4-dependent.CONCLUSIONSOur findings support a mechanistic contribution of impaired glymphatic function to tau accumulation and neuronal vulnerability in tauopathy. Pharmacological activation of AQP4 enhances glymphatic function, restores perivascular AQP4 organization, and ameliorates tau pathology, neurodegeneration, and gliosis. These findings identify AQP4-mediated glymphatic modulation as a disease-relevant and therapeutically tractable pathway for tau-related neurodegenerative disorders.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"35 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148476339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetic retinopathy: shaped by the \"hidden hand\" of post-translational modifications.","authors":"Ruihan Xiao,Meixia Zhang","doi":"10.1186/s13024-026-00973-x","DOIUrl":"https://doi.org/10.1186/s13024-026-00973-x","url":null,"abstract":"Diabetic retinopathy (DR), a leading cause of vision loss in working-age adults, is increasingly recognized as a combination of neurodegenerative and microvascular disease of the retina. Its pathological mechanism is complex, involving the regulation of multiple processes such as abnormal neovascularization, nerve damage, oxidative stress, and chronic inflammation. As a key molecular mechanism for regulating protein function, post-translational modifications (PTMs) can dynamically modulate the activity and function of core cells (including retinal endothelial cells, Müller cells, and pericytes) and related signaling molecules including various forms (e.g., phosphorylation, glycosylation, acetylation, methylation, ubiquitination, and SUMOylation), thereby deeply participating in the pathological progression of DR. In addition, PTMs play a crucial role in the regulating signaling pathways, including PI3K/Akt, MAPK, AMPK, NF-κB and JAK/STAT, in the development of DR. Moreover, increasing evidence demonstrates that targeting PTMs with small molecules, either as inhibitors or activators, can reverse protein misfolding and preserve neuroretinal integrity to halt the progression of DR. This review systematically summarizes the variation characteristics of different types of PTMs in DR, analyzes the involvement of PTMs on signaling cascade and cellular processes, reviews the association between ageing and PTMs, and sorts out the research progress of PTMs as potential diagnostic biomarkers and neuroprotective therapeutic targets for DR. It aims to offer a theoretical foundation for in-depth understanding of DR pathogenesis and the development of novel prevention and treatment strategies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"1 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148462615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The complex lipidome as a driver of tissue-specific pathology in adrenoleukodystrophy.","authors":"Stephan Kemp,Marc Engelen,Yorrick R J Jaspers","doi":"10.1186/s13024-026-00975-9","DOIUrl":"https://doi.org/10.1186/s13024-026-00975-9","url":null,"abstract":"X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal disorder caused by pathogenic variants in the ABCD1 gene, encoding a peroxisomal membrane transporter required for the import of very-long-chain fatty acids (VLCFA) into peroxisomes for degradation. ABCD1 deficiency leads to VLCFA accumulation in plasma and tissues. The resulting disease has a highly variable clinical presentation. In males, this manifests as cerebral demyelination, progressive myelopathy, and adrenal insufficiency, alone or in combination. Women predominantly develop myelopathy, while cerebral disease and adrenal insufficiency are rare, occurring almost exclusively in cases of extreme X-inactivation skewing toward the mutant allele. The lipid-mediated mechanisms linking VLCFA accumulation to tissue-specific pathology remain incompletely understood. Here, we review evidence that VLCFA-containing complex lipids, rather than free VLCFAs alone, are central mediators of tissue-specific pathology in ALD and discuss the therapeutic implications of this lipid-centric perspective. VLCFAs are incorporated into a broad range of complex lipids, including phosphatidylcholines, lysophosphatidylcholines, cholesterol esters, triacylglycerols, sphingomyelins, ceramides, and plasmalogens. The degree of lipid dysregulation increases with acyl chain length and saturation. VLCFA-containing lipid species correlate with disease severity across all clinical phenotypes. In the brain, VLCFA-containing phosphatidylcholines accumulate before demyelination onset, cholesterol ester accumulation is associated with neuroinflammatory cascades, and plasmalogen depletion reflects early oxidative damage. In the spinal cord, VLCFA-containing myelin lipids are associated with non-inflammatory axonopathy, mitochondrial dysfunction, and microglial phagocytic activation. In the adrenal gland, VLCFA accumulation in cholesterol ester-rich lipid droplets impairs ACTH receptor signaling and sequesters cholesterol from steroidogenic pathways. Enzymatic regulators of VLCFA homeostasis, including ELOVL1, SCD1, and the omega-oxidation enzymes CYP4F2 and CYP4F3B, are potential therapeutic targets for substrate reduction. Plasma VLCFA-lipid profiles correlate with disease severity across all affected tissues, positioning lipidomic profiling as a potential clinical instrument for risk stratification and treatment monitoring. Secondary lipid mediators amplify primary VLCFA toxicity through distinct, cell-type-specific pathways. The near-exclusive occurrence of cerebral ALD and adrenal insufficiency in women with extreme X-inactivation skewing suggests that partial reduction of the VLCFA lipid burden, rather than complete normalization, may be sufficient to prevent severe disease manifestations. This has direct implications for substrate-reduction therapy development.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"348 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148462655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Passive amyloid-β immunotherapy in Alzheimer's disease: a multicellular clearance system beyond plaque removal.","authors":"Xiaoni Zhan,Chenchen Liu,Changjiang Yu,Nils Lindblom,Tomas Deierborg,Asgeir Kobro-Flatmoen,Gunnar K Gouras,Gehua Wen","doi":"10.1186/s13024-026-00972-y","DOIUrl":"https://doi.org/10.1186/s13024-026-00972-y","url":null,"abstract":"Passive immunotherapy targeting amyloid-β (Aβ) has emerged as a major therapeutic strategy for Alzheimer's disease (AD), yet its clinical benefits remain modest and are frequently accompanied by vascular adverse events such as amyloid-related imaging abnormalities (ARIA). While the removal of extracellular Aβ plaques is associated with therapeutic efficacy, accumulating evidence suggests that additional cellular and vascular mechanisms may also contribute to complementary therapeutic outcomes alongside plaque removal. Recent studies show that Aβ antibodies are broadly distributed within the brain and interact with multiple neural and immune cell populations, rather than being limited to Aβ plaques. These observations support an expanded view of passive Aβ immunotherapy as a multicellular coordinated clearance process. Aβ antibodies engage diverse cellular and anatomical compartments, including neurons, glial cells, perivascular macrophages, peripheral immune cells, and meningeal lymphatic pathways, thereby influencing Aβ dynamics across intracellular and extracellular pools. Within this framework, therapeutic outcomes are influenced not only by plaque clearance but also by interactions between Aβ antibodies and cellular and anatomical compartments that regulate Aβ clearance and treatment-associated vascular response. This perspective may help explain variability in clinical efficacy and the emergence of vascular side effects, while also providing additional considerations for optimizing Aβ antibody design and therapeutic strategies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"64 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148462191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transplantation of human iPSC-derived microglia ameliorates neuropathology and circuit dysfunction in progranulin-deficient mice.","authors":"Hayk Davtyan, Sarah Naguib, Yuliya Voskobiynyk, Jean Paul Chadarevian, Joia K Capocchi, Jeannie L Giacchino, Ghazaleh Eskandari-Sedighi, Vivianna DeNittis, Jeremy B Ford, Ani Agababian, Jasmine Nguyen, Alina L Chadarevian, Madison S Sutherland, Sepideh Kiani Shabestari, Kayla Tran, Bret Holt, Alissa L Nana, Jiasheng Zhang, Salvatore Spina, Man Ying Wong, Lea T Grinberg, William W Seeley, Eric Huang, Claire D Clelland, Shiaoching Gong, Li Fan, Jeanne T Paz, Mathew Blurton-Jones, Li Gan","doi":"10.1186/s13024-026-00978-6","DOIUrl":"10.1186/s13024-026-00978-6","url":null,"abstract":"<p><p>Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglial progenitors into progranulin (Grn)-deficient mice. We find that engraftment of wild-type, but not Grn-deficient, human microglia restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because human microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atypical chemokine receptor 3 regulates synaptic removal in disease astrocytes.","authors":"V Giusti, J Park, E Giusto, L Masatti, P Ramos-Gonzalez, L Iovino, M Sandre, A Emmi, G Kaur, E Coletto, Zoë P Van Acker, W Annaert, E Calura, F Petrelli, A Porzionato, R De Caro, F Cavaliere, W S Chung, L Civiero","doi":"10.1186/s13024-026-00976-8","DOIUrl":"https://doi.org/10.1186/s13024-026-00976-8","url":null,"abstract":"<p><p>Astrocytes participate in the clearance of obsolete or unwanted neuronal synapses. However, the molecular machinery involved in synapse recognition remains unclear, particularly in pathological conditions. Here, we investigated the phagocytic process of astrocytes through individual gene silencing using a druggable gene library. Our study demonstrates that the Atypical chemokine receptor 3 (Ackr3) is a major player of astrocyte-mediated synapse engulfment. Mechanistically, we showed that Ackr3 recognizes phosphatidylethanolamine (PE)-bound C-X-C motif chemokine 12 (CXCL12) at synaptic terminals, thus serving as a novel marker of synaptic dysfunction. Notably, both ACKR3 and CXCL12 are upregulated in post-mortem brains of Alzheimer's disease (AD) patients, and AD mouse models. Genetic downregulation of Ackr3 in AD mice significantly reduces astrocyte-mediated synaptic elimination and rescues pathological phenotypes, including synapse loss and cognitive impairment. Overall, this work unveils a novel, possibly targetable mechanism of astrocyte-mediated synaptic engulfment implicated in neurodegenerative disease.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breaking the glial loop: astrocytic PAD2 and citrullinated vimentin drive microglial dysfunction in Alzheimer's disease.","authors":"Jeff Y L Lam,Guojun Bu","doi":"10.1186/s13024-026-00974-w","DOIUrl":"https://doi.org/10.1186/s13024-026-00974-w","url":null,"abstract":"Zhang et al. reveal that astrocytic PAD2-mediated citrullination of vimentin drives a TLR4-dependent pro-inflammatory loop in microglia, linking glial crosstalk to impaired amyloid clearance and identifying a potential therapeutic and biomarker pathway in Alzheimer's disease.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"217 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148432600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the genetic imperfections of Lewy body dementia.","authors":"Molly M Watkins,Gisela Xhafkollari,Na Zhao,Owen A Ross","doi":"10.1186/s13024-026-00961-1","DOIUrl":"https://doi.org/10.1186/s13024-026-00961-1","url":null,"abstract":"Lewy body dementia (LBD) is a clinically and pathologically complex neurodegenerative disease. Its etiology remains poorly understood and, as such, it is likely underdiagnosed in clinical practice. Clinically, LBD is defined by fluctuations in cognition, visual hallucinations, rapid eye movement (REM) sleep behavior disorder (RBD), and motor dysfunction. The disease is pathologically defined by the presence of Lewy bodies in the brain, which are protein aggregates made up of misfolded α-synuclein; however, co-pathologies are often present and greatly complicate both symptom presentation and research interpretation. This heterogeneous pathology paired with overlapping clinical features of Alzheimer's disease and Parkinson's disease hinder diagnostic clarity. With no specific biological biomarkers currently identified, it is the hope that genetics can help with diagnosis and to clarify the pathomechanistic nature of this multifaceted disorder. Through rare familial studies, SNCA, the gene which encodes α-synuclein, was implicated in disease risk and development, underscoring its central role in α-synucleinopathies. Shortly after this discovery, a genome wide association study (GWAS) confirmed this risk, and identified two other major genes, APOE and GBA, to be associated with LBD. The APOE ε4 allele, which is a well-established risk factor for AD, is also associated with an increased risk for LBD. This common association demonstrates that APOE is implicated in a broader role in neurodegenerative disease pathogenesis. Meanwhile, GBA mutations, which are associated with lysosomal dysfunction and are also a known risk factor for PD, are linked to a more severe cognitive decline and earlier disease onset. However, even with these advances, our understanding of LBD's genetic architecture remains incomplete. Overcoming these limitations will require larger, more diverse study cohorts, comprehensive analyses, technological advances, and improved phenotyping upon clinical presentation of disease. Current clinical diagnostic strategies often struggle to capture the full spectrum of LBD symptoms and commonly lead to misdiagnosis/misclassification. By combining genetic data with improved phenotyping and the latest novel technologies, we can greatly improve our mechanistic understanding of LBD. These insights will not only improve diagnostic accuracy but will also lead to the development of disease modifying treatments specifically designed to best treat each individual patient.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"230 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148408125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The human LRRK2-R1441G mutation drives age-dependent oxidative stress and mitochondrial dysfunction in dopaminergic neurons.","authors":"Yuanxin Chen, Lianteng Zhi, Shiquan Cui, Huaixin Wang, Chenbo Zeng, Hui Zhang","doi":"10.1186/s13024-026-00969-7","DOIUrl":"10.1186/s13024-026-00969-7","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial dysfunction and oxidative stress are central to the pathogenesis of Parkinson's disease (PD), particularly affecting substantia nigra pars compacta (SNc) dopamine (DA) neurons. Here, we investigate how the R1441G mutation in leucine-rich repeat kinase 2 (LRRK2), a key genetic contributor to familial and sporadic PD, impacts mitochondrial function in midbrain DA neurons.</p><p><strong>Methods: </strong>We employed a BAC transgenic mouse model overexpressing human LRRK2-R1441G (BAC-hR1441G) and crossed it with TH-mito-roGFP mice to enable mitochondria-targeted redox imaging specifically in DA neurons. Acute midbrain slices from 3-, 6-, and 10-month-old mice were imaged using two-photon microscopy to assess mitochondrial oxidative stress. In parallel, mitochondrial respiratory function, membrane potential flickering events, and expression of uncoupling proteins (UCP4/UCP5) were analyzed. Spatial transcriptomic profiling was performed using the GeoMx® Digital Spatial Profiler to uncover associated molecular alterations.</p><p><strong>Results: </strong>We observed a progressive increase in mitochondrial oxidative stress in SNc DA neurons of BAC-hR1441G mice at 3, 6, and 10 months of age. This was accompanied by reduced respiratory complex activity, attenuated mitochondrial membrane potential flickering, and diminished expression of UCP4 and UCP5. Spatial transcriptomic analysis revealed dysregulation of genes linked to mitochondrial uncoupling, calcium signaling, and redox regulation in BAC-hR1441G SNc DA neurons.</p><p><strong>Conclusions: </strong>These findings reveal an age-dependent progression of mitochondrial dysfunction in BAC-hR1441G SNc DA neurons. Dysregulation of calcium channels and uncoupling proteins emerges as a key mechanism contributing to bioenergetic failure, suggesting potential therapeutic targets to mitigate PD progression.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148397402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}