NPJ Parkinson's Disease最新文献_第8页

Prediction of all-cause mortality in Parkinson’s disease with explainable artificial intelligence using administrative healthcare data 利用行政医疗数据用可解释的人工智能预测帕金森病的全因死亡率

IF 8.7 1区医学

NPJ Parkinson's Disease Pub Date : 2025-06-02 DOI: 10.1038/s41531-025-01007-x

You Hyun Park, Yong Wook Kim, Dae Ryong Kang, Sang Chul Lee, Seo Yeon Yoon

{"title":"Prediction of all-cause mortality in Parkinson’s disease with explainable artificial intelligence using administrative healthcare data","authors":"You Hyun Park, Yong Wook Kim, Dae Ryong Kang, Sang Chul Lee, Seo Yeon Yoon","doi":"10.1038/s41531-025-01007-x","DOIUrl":"https://doi.org/10.1038/s41531-025-01007-x","url":null,"abstract":"Many studies have reported increased mortality risk in patients with Parkinson’s disease (PD), but few have investigated the risk factors for PD mortality, including medical and socioeconomic factors. We applied an explainable artificial intelligence (XAI) model to predict long-term all-cause mortality in patients with PD using administrative healthcare data collected at PD diagnosis. Among seven machine learning algorithms, XGBoost achieved the best performance (10-year area under the receiver operating characteristic curve (AUROC): 0.836; 5-year AUROC: 0.894). The most important contributing feature to PD mortality was age, followed by male sex and pneumonia. Using XAI models, the nonlinear association between contributing factors and PD mortality was assessed, and an optimal target value to reduce mortality was found. In addition, prediction of individualized 10-year mortality risk for each PD participant was possible. Our XAI modeling pipeline demonstrated the feasibility to predict long-term mortality in patients with PD using preexisting healthcare data.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"81 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201944","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}

引用次数: 0

Central biogenic amine deficiency with concomitant exploratory behavioral deficits in Dnajc12 knock-out mice Dnajc12基因敲除小鼠中枢生物胺缺乏伴探索性行为缺陷

IF 8.7 1区医学

NPJ Parkinson's Disease Pub Date : 2025-05-30 DOI: 10.1038/s41531-025-00991-4

Isaac Bul Deng, Jordan Follett, Jesse D. Fox, Shannon Wall, Matthew J. Farrer

{"title":"Central biogenic amine deficiency with concomitant exploratory behavioral deficits in Dnajc12 knock-out mice","authors":"Isaac Bul Deng, Jordan Follett, Jesse D. Fox, Shannon Wall, Matthew J. Farrer","doi":"10.1038/s41531-025-00991-4","DOIUrl":"https://doi.org/10.1038/s41531-025-00991-4","url":null,"abstract":"Bi-allelic autosomal recessive pathogenic variants in DNAJC12 lead to a constellation of neurological features, including young-onset Parkinson’s disease. DNAJC12 is a co-chaperone for enzymes involved in biogenic amines synthesis. In vitro, we discovered overexpressed DNAJC12 forms a complex with guanine triphosphate cyclohydrolase 1 (GCH1), a rate-limiting enzyme in the synthesis of tetrahydrobiopterin, a cofactor for biogenic amine synthesis. We also confirm DNAJC12’s interaction with tyrosine (TH) and tryptophan hydroxylases, paramount for dopamine (DA) and serotonin (5-HT) synthesis. In-vitro knock-down of DNAJC12 with a siRNA destabilizes DNAJC12-TH-GCH1 complex, whereas reciprocal co-overexpression of TH and GCH1 increases endogenous DNAJC12. Dnajc12 knock-out mice (DKO) exhibit reduced exploratory behavior at 3 months of age in open-field testing. In striatal tissue, total DA and 5-HT, and electrically evoked DA release are all reduced, with enhanced phosphorylation of Th at Ser31 and Ser40. DKO mice present models to develop/refine therapeutics approaches for biogenic amines disorders.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183747","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}

引用次数: 0

Impulsive-compulsive behaviours and striatal neuroactivity in mildly parkinsonian rats under D2/3 agonist and L-DOPA treatment D2/3激动剂和左旋多巴治疗下轻度帕金森大鼠的冲动强迫行为和纹状体神经活动

IF 8.7 1区医学

NPJ Parkinson's Disease Pub Date : 2025-05-29 DOI: 10.1038/s41531-025-00996-z

Mirjam Wolfschlag, Elena Espa, Katrine Skovgård, Pär Halje, Maria Angela Cenci

{"title":"Impulsive-compulsive behaviours and striatal neuroactivity in mildly parkinsonian rats under D2/3 agonist and L-DOPA treatment","authors":"Mirjam Wolfschlag, Elena Espa, Katrine Skovgård, Pär Halje, Maria Angela Cenci","doi":"10.1038/s41531-025-00996-z","DOIUrl":"https://doi.org/10.1038/s41531-025-00996-z","url":null,"abstract":"Dopamine replacement therapy for Parkinson’s disease can induce impulsive-compulsive behaviours (ICBs). Here we compare the D2/3 agonist ropinirole and L-DOPA, given alone or combined, with regard to their potential to induce ICBs in rats sustaining bilateral striatal injections of 6-hydroxydopamine. Daily treatment with ropinirole (2.5 mg/kg), L-DOPA (24.0 mg/kg), or their combination was given for six weeks while animals were examined using tests of compulsive checking and motor stereotypies not previously used in the ICB literature. Independently of L-DOPA cotreatment, ropinirole induced a stereotyped hyperactivity pattern, compulsive checking, and maladaptive choices in the rat version of the Iowa gambling task. Compared to both L-DOPA and vehicle, ropinirole elicited a distinct pattern of striatal neuroactivity, shifting the expression of a cellular activity marker from dorsolateral to centro-medial regions. Our results reveal quite distinct profiles of ICBs and striatal activation upon treatment with ropinirole or L-DOPA, providing clues of therapeutic relevance to Parkinson’s ICBs.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"3 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176995","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}

引用次数: 0

Computer vision uncovers three fundamental dimensions of levodopa-responsive motor improvement in Parkinson’s disease 计算机视觉揭示了帕金森病左旋多巴反应性运动改善的三个基本维度

IF 8.7 1区医学

NPJ Parkinson's Disease Pub Date : 2025-05-28 DOI: 10.1038/s41531-025-00999-w

Florian Lange, Diego L. Guarin, Esther Ademola, Dalia Mahdy, Gabriela Acevedo, Thorsten Odorfer, Joshua K. Wong, Jens Volkmann, Robert Peach, Martin Reich

引用次数: 0

Complement C4 exacerbates astrocyte-mediated neuroinflammation and promotes α-synuclein pathology in Parkinson’s disease 补体C4加重星形胶质细胞介导的神经炎症并促进帕金森病α-突触核蛋白病理

IF 8.7 1区医学

NPJ Parkinson's Disease Pub Date : 2025-05-28 DOI: 10.1038/s41531-025-01005-z

Wenkai Zou, Liang Kou, Yiming Wang, Zongjie Jin, Nian Xiong, Tao Wang, Yun Xia

{"title":"Complement C4 exacerbates astrocyte-mediated neuroinflammation and promotes α-synuclein pathology in Parkinson’s disease","authors":"Wenkai Zou, Liang Kou, Yiming Wang, Zongjie Jin, Nian Xiong, Tao Wang, Yun Xia","doi":"10.1038/s41531-025-01005-z","DOIUrl":"https://doi.org/10.1038/s41531-025-01005-z","url":null,"abstract":"Complement C4, implicated in neuroinflammation and synaptic dysfunction, plays a poorly defined role in Parkinson’s disease (PD). Here, we demonstrate elevated C4 levels in PD patient plasma and the substantia nigra of α-synuclein preformed fibril (α-syn PFF)-injected mice, correlating with disease severity. α-syn PFF treatment induces complement C4 expression, particularly in neurons, with astrocytes further enhancing this response. Complement C4 was found to amplify astrocytic inflammatory responses, leading to increased neuronal apoptosis and synaptic damage. Additionally, conditioned media from astrocytes treated with α-syn PFF and complement C4 accelerated α-syn aggregation and synaptic loss in cultured neurons. In vivo, complement C4 exacerbated motor dysfunction, dopaminergic neuronal loss, and α-syn pathology in α-syn PFF-injected mice. These findings reveal that complement C4 significantly contributes to the neuroinflammatory environment and α-syn pathology in PD, highlighting its potential as a therapeutic target for mitigating neurodegeneration in this disorder.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"1118 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164929","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}

引用次数: 0

Mapping striatal functional gradients and associated gene expression in Parkinson’s disease with continuous cognitive impairment 绘制纹状体功能梯度和相关基因表达在帕金森病持续认知障碍

IF 8.7 1区医学

NPJ Parkinson's Disease Pub Date : 2025-05-28 DOI: 10.1038/s41531-025-01002-2

Xiaolu Li, Shuting Bu, Huize Pang, Hongmei Yu, Mengwan Zhao, Juzhou Wang, Yu Liu, Guoguang Fan

{"title":"Mapping striatal functional gradients and associated gene expression in Parkinson’s disease with continuous cognitive impairment","authors":"Xiaolu Li, Shuting Bu, Huize Pang, Hongmei Yu, Mengwan Zhao, Juzhou Wang, Yu Liu, Guoguang Fan","doi":"10.1038/s41531-025-01002-2","DOIUrl":"https://doi.org/10.1038/s41531-025-01002-2","url":null,"abstract":"Cognitive impairment in Parkinson’s disease is closely tied to striatal dysfunction, yet the neurobiological interface between macroscale connectivity and molecular signatures remains unexplored. This study characterizes striatal gradient organization and its genetic underpinnings across PD cognitive trajectories. We analyzed functional connectivity gradients in 126 PD patients (spanning the cognitive spectrum from normal cognition to dementia) and 40 healthy controls, correlating spatial patterns with neurotransmitter architecture and transcriptomic profiles. Three distinct striatal gradients emerged: Gradient 1 remains stable throughout disease progression and partially aligns with canonical striatal subdivisions. Gradient 2 represents a spatial continuum closely linked to dopaminergic innervation and becomes most pronounced in the dementia stage. Gradient 3 corresponds to cortico-striatal connectivity patterns implicated in both early and advanced cognitive deficits. Spatial transcriptomic and neuroimaging correlation analyses identified significant associations between cortico-striatal gradient disruptions and specific gene expression patterns. These findings provide valuable insights into striatal macro- and microstructural changes in PD and their role in cognitive impairment.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"5 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153484","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}

引用次数: 0

Chronic stress induces depression-like behaviors and Parkinsonism via upregulating α-synuclein 慢性应激通过上调α-突触核蛋白诱导抑郁样行为和帕金森病

IF 8.7 1区医学

NPJ Parkinson's Disease Pub Date : 2025-05-28 DOI: 10.1038/s41531-025-00998-x

Danhao Xia, Min Xiong, Yingxu Yang, Xin Wang, Qiang Chen, Sheng Li, Lanxia Meng, Zhentao Zhang

{"title":"Chronic stress induces depression-like behaviors and Parkinsonism via upregulating α-synuclein","authors":"Danhao Xia, Min Xiong, Yingxu Yang, Xin Wang, Qiang Chen, Sheng Li, Lanxia Meng, Zhentao Zhang","doi":"10.1038/s41531-025-00998-x","DOIUrl":"https://doi.org/10.1038/s41531-025-00998-x","url":null,"abstract":"Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the aggregation of α-synuclein (α-syn) and the nigrostriatal dopaminergic neuronal degeneration. Depression is one of the most common non-motor symptoms of PD patients. However, the pathogenic connection between PD and depression is not well understood. Herein, we report that chronic stress upregulates the expression of α-syn in the mouse brain. Overexpression of α-syn in the hippocampus replicates depressive-like phenotypes, whereas the genetic deletion of α-syn enhances resistance to chronic stress. Furthermore, chronic stress in early life promoted the deposition of α-syn aggregates in a transgenic mouse model that overexpresses human A53T mutant α-syn (A53T mice). Chronic stress also exacerbated dopaminergic degeneration and motor impairments in A53T mice. Strikingly, α-syn inclusions were also observed in the brains of some aged non-transgenic mice subjected to chronic stress. Together, our findings suggest that chronic stress upregulates α-synuclein expression, resulting in depression-like behaviors and parkinsonism.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"58 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153578","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}

引用次数: 0

T cell responses towards PINK1 and α-synuclein are elevated in prodromal Parkinson’s disease T细胞对PINK1和α-突触核蛋白的反应在前驱帕金森病中升高

IF 8.7 1区医学

NPJ Parkinson's Disease Pub Date : 2025-05-26 DOI: 10.1038/s41531-025-01001-3

Emil Johansson, Antoine Freuchet, Gregory P. Williams, Tanner Michealis, April Frazier, Irene Litvan, Jennifer G. Goldman, Roy N. Alcalay, David G. Standaert, Amy W. Amara, Natividad Stover, Edward A. Fon, Ronald B. Postuma, John Sidney, David Sulzer, Cecilia S. Lindestam Arlehamn, Alessandro Sette

{"title":"T cell responses towards PINK1 and α-synuclein are elevated in prodromal Parkinson’s disease","authors":"Emil Johansson, Antoine Freuchet, Gregory P. Williams, Tanner Michealis, April Frazier, Irene Litvan, Jennifer G. Goldman, Roy N. Alcalay, David G. Standaert, Amy W. Amara, Natividad Stover, Edward A. Fon, Ronald B. Postuma, John Sidney, David Sulzer, Cecilia S. Lindestam Arlehamn, Alessandro Sette","doi":"10.1038/s41531-025-01001-3","DOIUrl":"https://doi.org/10.1038/s41531-025-01001-3","url":null,"abstract":"A role of the immune system in Parkinson’s disease (PD) progression has long been suspected due to the increased frequency of activated glial cells and infiltrating T cells in the substantia nigra. It was previously reported that PD donors have increased T cell responses towards PINK1 and α-synuclein (α-syn), two Lewy body-associated proteins. Further, T cell reactivity towards α-syn was highest closer to disease onset, highlighting that autoreactive T cells might play a role in PD pathogenesis. However, whether T cell autoreactivity is present during prodromal PD is unknown. Here, we investigated T cell responses towards PINK1 and α-syn in donors at high risk of developing PD (i.e. prodromal PD: genetic risk, hyposmia, and or REM sleep behavior disorder), in comparison to PD and healthy control donors. T cell reactivity to these two autoantigens was detected in prodromal PD at levels comparable to those detected in individuals with clinically diagnosed PD. Aligned with the increased incidence of PD in males, we found that males with PD, but not females, had elevated T cell reactivity compared to healthy controls. However, among prodromal PD donors, males and females had elevated T cell responses. These differing trends in reactivity highlights the need for further studies of the impact of biological sex on neuroinflammation and PD progression.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"4 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145882","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}

引用次数: 0

Oligodendrocyte-astrocyte crosstalk in Parkinson’s disease mediates neuronal ferroptosis via the FGF signaling pathway 帕金森病少突胶质细胞-星形胶质细胞串聊通过FGF信号通路介导神经元铁下垂

IF 8.7 1区医学

NPJ Parkinson's Disease Pub Date : 2025-05-23 DOI: 10.1038/s41531-025-00995-0

Sen Zhang, Min Yan, Xing Jiang, Youhan Liu, Wen Ma, Ling Ding, Zhimin Lu, Ying Luo, Xuewen Tian, Qinglu Wang

{"title":"Oligodendrocyte-astrocyte crosstalk in Parkinson’s disease mediates neuronal ferroptosis via the FGF signaling pathway","authors":"Sen Zhang, Min Yan, Xing Jiang, Youhan Liu, Wen Ma, Ling Ding, Zhimin Lu, Ying Luo, Xuewen Tian, Qinglu Wang","doi":"10.1038/s41531-025-00995-0","DOIUrl":"https://doi.org/10.1038/s41531-025-00995-0","url":null,"abstract":"Parkinson’s disease (PD), as a neurodegenerative disorder, is characterized primarily by damage to the central nervous system, accompanied by astrocyte dysfunction and the activation of ferroptosis. Recent studies have shown that oligodendrocytes also exhibit functional abnormalities in the brains of PD patients and are involved in the ferroptotic process. However, it remains unclear whether there is an interaction between oligodendrocytes and astrocytes and how they induce neuronal ferroptosis. Here, we employed single-nucleus sequencing and spatial transcriptomics to characterize the intercellular communication network between oligodendrocytes and astrocytes in the PD environment. Among these, astrocytes are the primary recipients of signals sent by oligodendrocytes in the FGF (Fibroblast growth factors) signaling pathway. In PD, the communication intensity is weakened, involving FGF1 and FGF9 and their receptors FGFR1, FGFR2, and FGFR3. Subsequently, we further validated the significant activation of mitochondrial oxidative phosphorylation processes within oligodendrocytes and astrocytes in PD mice, and that astrocytes might also involve the interaction of Mt1 and Ca2+. Additionally, we demonstrated a significant reduction in the number of DA neurons in the SN region and a notable activation of ferroptosis, alongside a significant decrease in the antioxidant pathway NRF2/SLC7A11/GPX4. In summary, our data elucidate that ferroptosis in the midbrain SN region preferentially occurs in astrocytes under the dysregulation of oligodendrocytes, leading to ferroptosis in DA neurons. Thus, our study highlights the crucial role of oligodendrocyte-astrocyte crosstalk in driving neuronal inactivation and inflammatory expansion in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"14 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123004","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}

引用次数: 0

Rational selection of the monoclonal α-synuclein antibody amlenetug (Lu AF82422) for the treatment of α-synucleinopathies 合理选择单克隆α-突触核蛋白抗体amlenetug （Lu AF82422）治疗α-突触核蛋白病

IF 8.7 1区医学

NPJ Parkinson's Disease Pub Date : 2025-05-22 DOI: 10.1038/s41531-024-00849-1

Pekka Kallunki, Florence Sotty, Katarina Willén, Michal Lubas, Laurent David, Malene Ambjørn, Ann-Louise Bergström, Louise Buur, Ibrahim Malik, Steffen Nyegaard, Thomas Thiilmark Eriksen, Berit O. Krogh, Jeffrey B. Stavenhagen, Kathrine J. Andersen, Lars Ø. Pedersen, Ersoy Cholak, Edward N. van den Brink, Rik Rademaker, Tom Vink, David Satijn, Paul W.H.I. Parren, Søren Christensen, Line R. Olsen, Josefine N. Søderberg, Sandra Vergo, Allan Jensen, Jan Egebjerg, Pernille Gry Wulff-Larsen, Mikkel N. Harndahl, Dina S. M. Damlund, Kaare Bjerregaard-Andersen, Karina Fog

{"title":"Rational selection of the monoclonal α-synuclein antibody amlenetug (Lu AF82422) for the treatment of α-synucleinopathies","authors":"Pekka Kallunki, Florence Sotty, Katarina Willén, Michal Lubas, Laurent David, Malene Ambjørn, Ann-Louise Bergström, Louise Buur, Ibrahim Malik, Steffen Nyegaard, Thomas Thiilmark Eriksen, Berit O. Krogh, Jeffrey B. Stavenhagen, Kathrine J. Andersen, Lars Ø. Pedersen, Ersoy Cholak, Edward N. van den Brink, Rik Rademaker, Tom Vink, David Satijn, Paul W.H.I. Parren, Søren Christensen, Line R. Olsen, Josefine N. Søderberg, Sandra Vergo, Allan Jensen, Jan Egebjerg, Pernille Gry Wulff-Larsen, Mikkel N. Harndahl, Dina S. M. Damlund, Kaare Bjerregaard-Andersen, Karina Fog","doi":"10.1038/s41531-024-00849-1","DOIUrl":"https://doi.org/10.1038/s41531-024-00849-1","url":null,"abstract":"Amlenetug (Lu AF82422) is a human monoclonal antibody targeting α-synuclein in clinical development for multiple system atrophy. We describe a series of studies that characterize its functional properties and supported its selection as a viable clinical candidate. Amlenetug inhibits seeding induced in mouse primary neurons by various α-synuclein fibrillar assemblies and by aggregates isolated from MSA brain homogenate. In vivo, both co-injection of amlenetug with α-synuclein assemblies in mouse brain and peripheral administration inhibit α-synuclein seeding. Amlenetug inhibits uptake of α-synuclein seeds as well as accumulation of C-terminal truncated α-synuclein seeds and demonstrates binding to monomeric, aggregated, and truncated forms of human α-synuclein. The epitope of amlenetug was mapped to amino acids 112-117 and further characterized by crystallographic structure analysis. Based on our data, we hypothesize that targeting α-synuclein will potentially slow further disease progression by inhibiting further pathology development but be without impact on established pathology and symptoms.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"45 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113977","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}

引用次数: 0