NPJ Parkinson's Disease最新文献

{"title":"Identifying the neural correlates of voluntary stopping in people with Parkinson’s disease using a Virtual Reality gait paradigm","authors":"Eileen Gülke,Christopher Coppin,John Azizi,Hanna Braaß,Lachlan Churchill,Yanqiu Tian,Simon J. G. Lewis","doi":"10.1038/s41531-026-01514-5","DOIUrl":"https://doi.org/10.1038/s41531-026-01514-5","url":null,"abstract":"Abstract Freezing of Gait (FOG) is a disabling feature of Parkinson’s disease (PD). However, the neural mechanisms underlying voluntary stopping impairments remain unclear. This study used a validated Virtual Reality (VR) gait paradigm to investigate the neural correlates of cued voluntary stopping in 15 PD participants with FOG, 10 PD participants without FOG, and 12 healthy controls. PD participants were assessed on and off dopaminergic medication. Blood-oxygen-level-dependent (BOLD) signals during voluntary stopping were compared with walking and rest periods. In the OFF state, PD participants showed impaired voluntary stopping relative to healthy controls, relying predominantly on the Supplementary Motor Area (SMA). Dopaminergic medication restored stopping performance to levels comparable to healthy controls and was associated with broader recruitment of occipital, cerebellar, and inferior frontal regions. Freezers exhibited greater stopping deficits and relied on the SMA in both medication states. They also demonstrated reduced functional connectivity across occipital, temporal, and cerebellar regions in the ON state and recruited fewer cortical regions compared to non-freezers, particularly in the OFF state. The findings suggest that PD participants with FOG fail to engage a disseminated voluntary stopping network. Future work should explore interactions between the stopping network and brainstem gait and balance systems.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"13 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148894037","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":"A pharmacogenetic framework for disease-modifying clinical trials in Parkinson’s disease","authors":"Rowan Gurney,Huw Morris,Thomas Foltynie","doi":"10.1038/s41531-026-01552-z","DOIUrl":"https://doi.org/10.1038/s41531-026-01552-z","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"3 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148894035","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":"A novel dual-target approach for Parkinson’s disease therapy by the novel immunomodulator 3-monothiopomalidomide","authors":"Maria Francesca Palmas, Khosro Aminzadeh, Matteo Runfola, Pathik Parekh, Clara Porcedda, David Tweedie, Luca Casula, Maria Cristina Cardia, Jacopo Marongiu, Michela Etzi, Francesco Lai, Marcello Serra, Valeria Crippa, Augusta Pisanu, Valeria Sogos, Alfonso De Simone, Dong Seok Kim, Nigel H. Greig, Anna R. Carta","doi":"10.1038/s41531-026-01549-8","DOIUrl":"https://doi.org/10.1038/s41531-026-01549-8","url":null,"abstract":"α-Synuclein (αSyn) aggregation is a central driver for Parkinson’s disease (PD), leading to the formation of toxic oligomeric species that promote microglial reactivity and establish a self-sustaining cycle of neuroinflammation and neurodegeneration. This process accelerates dopaminergic neuron loss in the substantia nigra and contributes to motor and cognitive deficits. Targeting both αSyn aggregation and inflammation represents a promising therapeutic strategy. This study evaluated 3-monothiopomalidomide (3MP), a novel immunomodulatory imide drug with improved safety over Pomalidomide. In vitro, 3MP reduced αSyn–induced neuronal death, microglial activation, and inflammation. Thioflavin T assay and Thioflavin S staining in SH-SY5Y cells showed significant inhibition of αSyn aggregation. In vivo, chronic administration in a αSyn-based PD rat model preserved dopaminergic neurons, improved motor and cognitive function, reduced αSyn aggregates and neuroinflammation in the midbrain and anterior cingulate cortex. Overall, 3MP shows strong dual-action potential by modulating both αSyn aggregation and neuroinflammation, supporting its development as a disease-modifying therapy for PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"150 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899550","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":"Environmental neurotoxicant-induced mitochondrial dysfunction impairs the nuclear pore complex and nucleocytoplasmic transport in Parkinson’s disease pathogenesis","authors":"Zainab Riaz, Yuan-Teng Chang, Ahyoung Jang, Gabriel S. Richardson, Manikandan Samidurai, Gary Zenitsky, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G. Kanthasamy","doi":"10.1038/s41531-026-01553-y","DOIUrl":"https://doi.org/10.1038/s41531-026-01553-y","url":null,"abstract":"Parkinson’s disease (PD) pathogenesis elicits diverse cellular dysregulations, including mislocalized transcription factors and nuclear envelope malformations in affected dopaminergic neurons. Environmental risk factors, particularly mitochondrial toxicants and neurotoxicant exposures, are increasingly recognized as important contributors to PD susceptibility and progression by promoting oxidative stress and mitochondrial impairment in vulnerable nigrostriatal dopaminergic neurons. However, the contribution of channel-forming nucleoporins (Nups) to environmental neurotoxicant- and mitochondrial dysfunction-related neurodegenerative processes remains unexplored. Herein, we identified pathological abnormalities in both the levels and cellular distribution of specific Nups, which are key components of the nuclear pore complex, in mitochondria-impaired dopaminergic neurons in PD. We observed that mitochondrial dysfunction reduces the expression of nuclear basket Nups153 and 50, as well as the scaffold Nup107, and disrupts the localization of Ran GTPase in in vitro and in vivo dopaminergic neuron models of mitochondrial dysfunction in PD. Importantly, the nuclear pore central channel component Nup62 mislocalizes and accumulates in the cytoplasm of mitochondria-stressed dopaminergic neurons. Mitochondrial stress also interferes with bidirectional nucleocytoplasmic transport of proteins mediated by Nups in dopaminergic neuronal cells. We observed Nup pathology and Ran gradient loss in nigral dopaminergic neurons of PD patient brains, which highlights the clinical relevance of nuclear pore dysfunction. Collectively, these findings provide direct evidence that environmental neurotoxicant-linked mitochondrial dysfunction can impair the nuclear pore complex and nucleocytoplasmic transport, mechanistically linking Nup-related abnormalities to dopaminergic neurodegeneration and PD pathogenesis.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"30 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899540","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":"Coffee and Parkinson’s disease: associations by CYP1A2 genotype and sex in UK Biobank","authors":"Jieping Wang, Huanyu Wang, Kang wan, Ruwen Wang, Shanshan Guo, Fuyi Ma, Yang Xiang, Hao Ma, Geng Zong, Xiao Zhi, Xiaoli Tian, Guodong Zhou, Ru Wang","doi":"10.1038/s41531-026-01519-0","DOIUrl":"https://doi.org/10.1038/s41531-026-01519-0","url":null,"abstract":"Coffee consumption has been associated with Parkinson’s disease (PD), but findings remain inconsistent. We examined whether this association differs by CYP1A2 genotype and sex in 435,551 UK Biobank participants free of PD at baseline. During a median follow-up of 15.7 years, 3319 incident PD cases were identified. In overall analyses, coffee intake was not associated with PD risk. However, coffee intake significantly interacted with CYP1A2 genotype. Among AA carriers, coffee intake below 5 cups/day was associated with lower PD risk (HR 0.83, 95% CI 0.74–0.93), and spline analyses indicated a nonlinear association with the lowest risk at around 3 cups/day. In contrast, high coffee intake (≥5 cups/day) was associated with higher PD risk in AC carriers (HR 1.43, 95% CI 1.11–1.85) and CC carriers (HR 1.84, 95% CI 1.08–3.11). Sex-stratified analyses showed that the inverse association in AA carriers was more evident in women, whereas increased risk at high intake among AC/CC carriers was mainly observed in men. These findings support heterogeneity in the association between coffee intake and PD risk according to CYP1A2 genotype.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"35 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899558","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":"Biological heterogeneity in Parkinson's disease: implications for MRI-based patient stratification.","authors":"Marta M Pokotylo, Norbert Brüggemann, Jannik Prasuhn","doi":"10.1038/s41531-026-01544-z","DOIUrl":"10.1038/s41531-026-01544-z","url":null,"abstract":"<p><p>Parkinson's disease is increasingly recognized as a heterogeneous syndrome characterized by diverse pathological processes and clinical manifestations. Here, we propose a multidimensional framework to assess this heterogeneity, with each dimension potentially captured using advanced magnetic resonance imaging techniques. The framework comprises dominant pathological processes, spatial distribution patterns of pathology across brain regions, propagation architecture, temporal dynamics of disease progression, co-pathology burden, and system response and resilience mechanisms.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"12 1","pages":""},"PeriodicalIF":8.5,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840952","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":"Matters arising: bridging predictive algorithms and clinical practice in DBS contact selection.","authors":"Annabel van der Weide, Yarit Wiggerts, Deborah Hubers, Bart J Keulen, Martijn G J de Neeling, Mariëlle J Stam, Bernadette C M van Wijk, Maarten Bot, Rick Schuurman, Rob M A de Bie, Martijn Beudel","doi":"10.1038/s41531-026-01496-4","DOIUrl":"10.1038/s41531-026-01496-4","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"12 1","pages":""},"PeriodicalIF":8.5,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840950","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":"Reply to: Bridging predictive algorithms and clinical practice in DBS contact selection.","authors":"Marjolein Muller, Ioannis U Isaias, Eduardo M Moraud, M Fiorella Contarino","doi":"10.1038/s41531-026-01534-1","DOIUrl":"10.1038/s41531-026-01534-1","url":null,"abstract":"<p><p>We thank the authors (Weide et al.¹) for their evaluation of our algorithm, which predicts optimal deep-brain stimulation contact points in Parkinson's disease. Their analysis on an independent dataset highlights practical challenges of translating predictive tools into routine clinical use. Here, we clarify key methodological points, discuss the robustness of the algorithm, and emphasize the need for broader validation across diverse clinical centers to fully demonstrate its utility.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"12 1","pages":""},"PeriodicalIF":8.5,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840946","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":"Single cell transcriptomics reveals enrichment of predicted aggregation-prone alpha-synuclein isoforms across synucleinopathies","authors":"E. Keats Shwab, Webb Pierson, Daniel C. Gingerich, Zhaohui Man, Sapir Margalit, Dean Yona, Asaf Sivan, Julia Gamache, Geidy E. Serrano, Thomas G. Beach, Yuval Ebenstein, Roy Beck, Ornit Chiba-Falek","doi":"10.1038/s41531-026-01548-9","DOIUrl":"https://doi.org/10.1038/s41531-026-01548-9","url":null,"abstract":"Alpha-synuclein (α-Syn) is the primary component of Lewy bodies, the pathological hallmark of neurodegenerative synucleinopathies, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Dysregulated expression of encoding gene SNCA has been associated with both disorders in short-read sequencing studies. However, such studies do not capture transcript isoform variation. Here, we combine SNCA-targeted long-read multiplexed arrays isoform sequencing (MAS-Iso-seq) with unbiased short-read single nucleus (sn) RNA-seq to simultaneously characterize the SNCA transcript isoform landscape and map isoform expression to specific cell subtypes in PD, DLB, and control tissues. This approach identified 327 SNCA transcript isoforms grouped into 50 unique splicing classes. We further identified an abundant class of transcript isoforms predicted to encode a novel α-Syn protein variant (α-Syn-115) and displaying increased proportional detection in excitatory neurons of PD and DLB, especially within several glutamatergic neuron subtypes. In silico structural modeling predicted greater aggregative propensity for α-Syn-115 than canonical α-Syn-140, suggesting that increased cytosolic α-Syn-115 could induce aggregation between heterogeneous α-Syn isoforms, potentially driving fibril formation and disease progression. Together, these findings provide new insight into α-Syn biology in synucleinopathies and suggest directions for potential treatment strategies targeting specific transcript and protein isoforms and disease-associated cell subtypes.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"38 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148853518","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":"Protein aggregation inhibitors induce divergent transcriptional responses in a cellular model of ɑ-synuclein seeded aggregation","authors":"Paulien Van Minsel, Chris Van den Haute, Eline Vonck, Shirine Hentati, Michele Curcio, Xinran Song, Qian Yu, Matthias Versele, Kenneth W. Young, Patrick Chaltin, Bernard Thienpont, Veronique Daniels, Veerle Baekelandt, Wouter Peelaerts","doi":"10.1038/s41531-026-01540-3","DOIUrl":"https://doi.org/10.1038/s41531-026-01540-3","url":null,"abstract":"Parkinson’s disease, dementia with Lewy Bodies, and multiple system atrophy are progressive neurodegenerative disorders marked by aggregation of alpha-synuclein (ɑSyn). Despite significant research efforts, effective therapeutic interventions remain elusive due to a limited understanding of the cellular effects of ɑSyn aggregation and propagation. This study presents a screening platform that combines an ɑSyn reporter assay with multiplexed single-cell RNA sequencing, enabling simultaneous high-throughput phenotypic screening and transcriptional profiling of compounds targeting ɑSyn-seeded aggregation. Compounds are profiled in both the absence and presence of αSyn aggregation, a design that distinguishes aggregation-dependent from compound-intrinsic transcriptional effects. We evaluated three αSyn aggregation inhibitors: Minzasolmin (UCB0599), Emrusolmin (Anle138b), and EGCG, revealing distinct compound effects on lipid metabolism and rRNA-processing pathways, with Minzasolmin producing the most pronounced effect on sterol biosynthesis genes. Notably, while EGCG effects were confined to cells with aggregated αSyn, Minzasolmin and Emrusolmin also produced transcriptional changes in cells without aggregated αSyn. The platform identified candidate genes that were no longer significantly differentially expressed upon the addition of the compound, relative to cells with seeded aggregation, demonstrating its potential to generate molecular signatures for benchmarking future hits. This platform bridges phenotypic screening and molecular pathway analysis, providing insights into druggable pathways for synucleinopathies.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"26 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148853684","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}