Pub Date : 2026-02-10DOI: 10.1038/s41531-026-01288-w
K. C. Biju, Enrique Torres Hernandez, Alison Michelle. Stallings, Ada C. Felix-Ortiz, Skanda K. Hebbale, Robert A. Clark
Olfactory dysfunction, often the earliest symptom of Parkinson’s disease (PD), can precede clinical diagnosis by over 20 years, yet its mechanism and link to α-synuclein pathology remain unclear. To understand the impact of α-synuclein pathology on the topographic olfactory sensory map that supports the detection and discrimination of particular odors, we created two double transgenic mouse models (α-Syn/M72 and α-Syn/P2) expressing tagged-M72 or tagged-P2 odor receptors in a human wild-type α-synuclein over-expressing background. We demonstrated that the sensory map is disrupted in these mice. Histological analysis showed a significant reduction in M72 and P2 olfactory sensory neurons (OSNs), with altered glomerular topographies as axons converged into supernumerary glomeruli of varying size and location. These findings suggest that α-synuclein overexpression impairs the mechanism guiding the convergence of OSN axons and thus formation of a precise olfactory sensory map. As OSNs in the nasal epithelium are accessible via non-invasive biopsy, they are a potential source of prodromal PD biomarkers.
{"title":"Olfactory sensory map is perturbed in a human wild-type α-synuclein overexpressing transgenic mouse model of Parkinson’s disease","authors":"K. C. Biju, Enrique Torres Hernandez, Alison Michelle. Stallings, Ada C. Felix-Ortiz, Skanda K. Hebbale, Robert A. Clark","doi":"10.1038/s41531-026-01288-w","DOIUrl":"https://doi.org/10.1038/s41531-026-01288-w","url":null,"abstract":"Olfactory dysfunction, often the earliest symptom of Parkinson’s disease (PD), can precede clinical diagnosis by over 20 years, yet its mechanism and link to α-synuclein pathology remain unclear. To understand the impact of α-synuclein pathology on the topographic olfactory sensory map that supports the detection and discrimination of particular odors, we created two double transgenic mouse models (α-Syn/M72 and α-Syn/P2) expressing tagged-M72 or tagged-P2 odor receptors in a human wild-type α-synuclein over-expressing background. We demonstrated that the sensory map is disrupted in these mice. Histological analysis showed a significant reduction in M72 and P2 olfactory sensory neurons (OSNs), with altered glomerular topographies as axons converged into supernumerary glomeruli of varying size and location. These findings suggest that α-synuclein overexpression impairs the mechanism guiding the convergence of OSN axons and thus formation of a precise olfactory sensory map. As OSNs in the nasal epithelium are accessible via non-invasive biopsy, they are a potential source of prodromal PD biomarkers.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"92 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152248","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}
Pub Date : 2026-02-07DOI: 10.1038/s41531-026-01280-4
Elisa Lilly Garulli, Timon Merk, Ghadi El Hasbani, Burçe Kabaoğlu, Rafaël De Sa, Ruben Behrsing, Dennis Doll, Michael Franz-Josef Schellenberger, Ibrahem Hanafi, Arend Vogt, Wolf-Julian Neumann, Chiara Palmisano, Ioannis Ugo Isaias, Yangfan Peng, Matthias Endres, Christoph Harms, Nikolaus Wenger
Gait deficits present an unresolved therapeutic challenge in Parkinson’s disease. At the behavioral level, symptoms exhibit heterogeneity, including bradykinesia and hypokinesia during cyclical limb movements, and sudden, involuntary interruptions in the gait sequence, known as freezing of gait. The neural activities driving these various deficits remain largely unknown. Here, we investigated the neural correlates of gait sequence interruptions with a deep phenotyping approach. For this, we transformed kinematic trajectories and cortical oscillations into continuous time series of neurobehavioral features. Next, we combined low-dimensional embedding with supervised classification to identify cortical oscillation features that drive gait deficits. In a rodent Parkinson’s disease model, our approach revealed that gait, akinesia, and stationary movements occupy distinct regions in the low-dimensional embedding space. Among the predominant features separating the states, Hjorth complexity and mobility modulated at akinesia onset. Additionally, we validated our findings in two Parkinson’s patients with freezing of gait, where neural features in STN recordings partially reflected the results in rodents. The presented neurobehavioral phenotyping approach is translational and can easily be generalized to the analysis of other complex movement disorders. Together, our results highlight specific neural features as potential biomarkers that may support the development of adaptive closed-loop algorithms for gait therapy in PD.
{"title":"Deep neurobehavioral phenotyping uncovers neural fingerprints of locomotor deficits in Parkinson’s disease","authors":"Elisa Lilly Garulli, Timon Merk, Ghadi El Hasbani, Burçe Kabaoğlu, Rafaël De Sa, Ruben Behrsing, Dennis Doll, Michael Franz-Josef Schellenberger, Ibrahem Hanafi, Arend Vogt, Wolf-Julian Neumann, Chiara Palmisano, Ioannis Ugo Isaias, Yangfan Peng, Matthias Endres, Christoph Harms, Nikolaus Wenger","doi":"10.1038/s41531-026-01280-4","DOIUrl":"https://doi.org/10.1038/s41531-026-01280-4","url":null,"abstract":"Gait deficits present an unresolved therapeutic challenge in Parkinson’s disease. At the behavioral level, symptoms exhibit heterogeneity, including bradykinesia and hypokinesia during cyclical limb movements, and sudden, involuntary interruptions in the gait sequence, known as freezing of gait. The neural activities driving these various deficits remain largely unknown. Here, we investigated the neural correlates of gait sequence interruptions with a deep phenotyping approach. For this, we transformed kinematic trajectories and cortical oscillations into continuous time series of neurobehavioral features. Next, we combined low-dimensional embedding with supervised classification to identify cortical oscillation features that drive gait deficits. In a rodent Parkinson’s disease model, our approach revealed that gait, akinesia, and stationary movements occupy distinct regions in the low-dimensional embedding space. Among the predominant features separating the states, Hjorth complexity and mobility modulated at akinesia onset. Additionally, we validated our findings in two Parkinson’s patients with freezing of gait, where neural features in STN recordings partially reflected the results in rodents. The presented neurobehavioral phenotyping approach is translational and can easily be generalized to the analysis of other complex movement disorders. Together, our results highlight specific neural features as potential biomarkers that may support the development of adaptive closed-loop algorithms for gait therapy in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"182 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135598","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}
Chronic intestinal inflammation is a key precursor to Parkinson’s disease (PD). Leucine-rich repeat kinase 2 R1628P variant (LRRK2R1628P) is a risk factor for PD in Asians. However, whether it drives the occurrence of intestinal inflammation remains elusive. Here, we report that LRRK2R1627P (the rat homolog) disrupts intestinal homeostasis during aging and toxin exposure in rats. Compared with age-matched wild-type rats, aging LRRK2R1627P rats exhibited shortened small intestine, reduced goblet cells, and abnormal epithelial cell junction structures. Mechanistically, these changes were induced by macrophage polarization toward a pro-inflammatory phenotype via TLR4/MyD88/NF-κB pathway, resulting in PD-associated intestinal pathology, including chronic inflammatory, decreased microbial diversity, and increased p-α-synuclein aggregation. LRRK2R1627P also enhanced susceptibility to lipopolysaccharide-induced intestinal inflammation. Remarkably, TLR4 inhibitor ameliorated the age-related disruption of intestinal homeostasis mediated by LRRK2R1627P. Using the LRRK2R1627P rats, this study reveals a cascading interplay among genetic susceptibility, age-related internal imbalance, and exogenous toxin exposure in PD pathology. These findings provide critical insights into how the dynamic interplay of multiple risk factors overwhelms the body’s compensatory thresholds, ultimately initiating the pathological process of neurodegeneration.
{"title":"LRRK2R1627P mutation amplifies environmental risk factors induced chronic inflammation and α-synuclein aggregation in the gut of rats","authors":"Shimin Pang, Jing Lu, Yanyan Wang, Chao Ying, Chunsong Zhao, Zhenyu Yue, Qiumei Yang, Piu Chan","doi":"10.1038/s41531-026-01281-3","DOIUrl":"https://doi.org/10.1038/s41531-026-01281-3","url":null,"abstract":"Chronic intestinal inflammation is a key precursor to Parkinson’s disease (PD). Leucine-rich repeat kinase 2 R1628P variant (LRRK2R1628P) is a risk factor for PD in Asians. However, whether it drives the occurrence of intestinal inflammation remains elusive. Here, we report that LRRK2R1627P (the rat homolog) disrupts intestinal homeostasis during aging and toxin exposure in rats. Compared with age-matched wild-type rats, aging LRRK2R1627P rats exhibited shortened small intestine, reduced goblet cells, and abnormal epithelial cell junction structures. Mechanistically, these changes were induced by macrophage polarization toward a pro-inflammatory phenotype via TLR4/MyD88/NF-κB pathway, resulting in PD-associated intestinal pathology, including chronic inflammatory, decreased microbial diversity, and increased p-α-synuclein aggregation. LRRK2R1627P also enhanced susceptibility to lipopolysaccharide-induced intestinal inflammation. Remarkably, TLR4 inhibitor ameliorated the age-related disruption of intestinal homeostasis mediated by LRRK2R1627P. Using the LRRK2R1627P rats, this study reveals a cascading interplay among genetic susceptibility, age-related internal imbalance, and exogenous toxin exposure in PD pathology. These findings provide critical insights into how the dynamic interplay of multiple risk factors overwhelms the body’s compensatory thresholds, ultimately initiating the pathological process of neurodegeneration.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"161 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135599","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}
Pub Date : 2026-02-03DOI: 10.1038/s41531-026-01275-1
Harini Sarva, Rajesh Pahwa, Jorge Hernandez-Vara, Mark A. Goldstein, Rupam Borgohain, Stewart A. Factor, Sandeep Inamdar, Damon Love, Carrie Hames, Yiyong Fu, Victor Mergel, Andrew Goldfine, Chandra Kumar, Steven P. Piccoli, Siu-Long Yao, Orest Hurko
Inhibition of cAbl tyrosine kinase reduces α-synuclein aggregation, protects dopaminergic neurons, and improves motor function in animal models of Parkinson’s Disease (PD). PROSEEK was a Phase 2, randomized, double-blind, placebo-controlled study of the effects on disease progression of Vodobatinib, a brain-penetrant c-Abl inhibitor, in 513 participants with early PD not on symptomatic treatment other than a stable dose of a MAO-B inhibitor. Recently diagnosed subjects with confirmatory Dopamine Transporter Single Photon Emission Computed Tomography (DaT-SPECT) scans were randomized to daily Vodobatinib 384 mg, 192 mg, or placebo. The primary endpoint in Part 1 was the change from baseline to Week 40 in the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III total score; Part 2 was an optional 36-week extension. There was a high, dose-related rate of early withdrawal. The mean score of completers in the placebo group was slightly lower than at baseline of the entire cohort. Comparisons with either dose group favored the placebo. Serum neurofilament light chains increased significantly in both Vodobatinib groups, supporting inefficacy in PD.
{"title":"Evaluation of c-Abl inhibitor vodobatinib in subjects with early Parkinson’s disease: a phase 2, randomized, double-blind, placebo-controlled study","authors":"Harini Sarva, Rajesh Pahwa, Jorge Hernandez-Vara, Mark A. Goldstein, Rupam Borgohain, Stewart A. Factor, Sandeep Inamdar, Damon Love, Carrie Hames, Yiyong Fu, Victor Mergel, Andrew Goldfine, Chandra Kumar, Steven P. Piccoli, Siu-Long Yao, Orest Hurko","doi":"10.1038/s41531-026-01275-1","DOIUrl":"https://doi.org/10.1038/s41531-026-01275-1","url":null,"abstract":"Inhibition of cAbl tyrosine kinase reduces α-synuclein aggregation, protects dopaminergic neurons, and improves motor function in animal models of Parkinson’s Disease (PD). PROSEEK was a Phase 2, randomized, double-blind, placebo-controlled study of the effects on disease progression of Vodobatinib, a brain-penetrant c-Abl inhibitor, in 513 participants with early PD not on symptomatic treatment other than a stable dose of a MAO-B inhibitor. Recently diagnosed subjects with confirmatory Dopamine Transporter Single Photon Emission Computed Tomography (DaT-SPECT) scans were randomized to daily Vodobatinib 384 mg, 192 mg, or placebo. The primary endpoint in Part 1 was the change from baseline to Week 40 in the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III total score; Part 2 was an optional 36-week extension. There was a high, dose-related rate of early withdrawal. The mean score of completers in the placebo group was slightly lower than at baseline of the entire cohort. Comparisons with either dose group favored the placebo. Serum neurofilament light chains increased significantly in both Vodobatinib groups, supporting inefficacy in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"97 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102076","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}
Pub Date : 2026-02-02DOI: 10.1038/s41531-026-01265-3
Kai Shi Lim, Maria Teresa Periñan, Elaine Guo Yan Chew, Paul Suhwan Lee, Fulya Akçimen, Jia Lun Lim, Mathew J. Koretsky, Manabu Funayama, Hiroyo Yoshino, Nobutaka Hattori, Rauan Kaiyrzhanov, Henry Houlden, Mariam Isayan, Yi Wen Tay, Tzi Shin Toh, Lei-Cheng Lit, Anis Nadhirah Khairul Anuar, Hans Xing Ding, Laurel Screven, Norlinah Mohamed Ibrahim, Chin-Hsien Lin, Han-Joon Kim, Jee-Young Lee, Sun Ju Chung, Jia Nee Foo, Eng-King Tan, Shen-Yang Lim, Ai Huey Tan, Sara Bandres-Ciga, Azlina Ahmad-Annuar, the Global Parkinson’s Genetics Program (GP2)
Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations, and in this study, the rare p.A419V variant was investigated across multiple ancestry cohorts comprising over 200,000 PD cases and controls. In cases of East Asian (EAS) ancestry, p.A419V was significantly associated with increased risk of PD (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), and was not in linkage disequilibrium with other LRRK2 coding variants. The variant was significantly associated with a lower age at PD onset in the study cohort, while a meta-analysis of the EAS cases indicated a similar, albeit non-significant trend. LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB29 and RAB32 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling.
LRRK2的常见和罕见变异影响不同人群的帕金森病（PD）风险，在本研究中，罕见的p.A419V变异在多个祖先队列中进行了调查，包括超过20万PD病例和对照组。在东亚（EAS）血统的病例中，p.A419V与PD风险增加显著相关（OR = 2.9; 95% CI: 1.66-5.10; p = 0.0002），并且与其他LRRK2编码变体不存在连锁不平衡。在研究队列中，该变异与较低的PD发病年龄显著相关，而对EAS病例的荟萃分析显示了类似的趋势，尽管不显著。LRRK2蛋白模型预测表明，RAB8A、RAB29和RAB32的结合位点在ARM结构域内与p.A419V变异位点非常接近。总之，这些发现证实了p.A419V在EAS人群中是一个重要的PD危险因素，并强调了ARM域中的疾病相关变异以及与LRRK2-RAB信号传导的联系。
{"title":"Association of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset","authors":"Kai Shi Lim, Maria Teresa Periñan, Elaine Guo Yan Chew, Paul Suhwan Lee, Fulya Akçimen, Jia Lun Lim, Mathew J. Koretsky, Manabu Funayama, Hiroyo Yoshino, Nobutaka Hattori, Rauan Kaiyrzhanov, Henry Houlden, Mariam Isayan, Yi Wen Tay, Tzi Shin Toh, Lei-Cheng Lit, Anis Nadhirah Khairul Anuar, Hans Xing Ding, Laurel Screven, Norlinah Mohamed Ibrahim, Chin-Hsien Lin, Han-Joon Kim, Jee-Young Lee, Sun Ju Chung, Jia Nee Foo, Eng-King Tan, Shen-Yang Lim, Ai Huey Tan, Sara Bandres-Ciga, Azlina Ahmad-Annuar, the Global Parkinson’s Genetics Program (GP2)","doi":"10.1038/s41531-026-01265-3","DOIUrl":"https://doi.org/10.1038/s41531-026-01265-3","url":null,"abstract":"Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations, and in this study, the rare p.A419V variant was investigated across multiple ancestry cohorts comprising over 200,000 PD cases and controls. In cases of East Asian (EAS) ancestry, p.A419V was significantly associated with increased risk of PD (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), and was not in linkage disequilibrium with other LRRK2 coding variants. The variant was significantly associated with a lower age at PD onset in the study cohort, while a meta-analysis of the EAS cases indicated a similar, albeit non-significant trend. LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB29 and RAB32 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"147 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102080","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}
Pub Date : 2026-01-31DOI: 10.1038/s41531-026-01273-3
Guan-Yu Zhu, Timon Merk, Konstantin Butenko, Zi-Xiao Yin, Ying-Chuan Chen, Ning-Fei Li, Thomas Binns, Ruo-Yu Ma, Ting-Ting Du, Yu-Ye Liu, Hu-Tao Xie, Lin Shi, An-Chao Yang, Fan-Gang Meng, Andrea A. Kühn, Jian-Guo Zhang, Wolf-Julian Neumann
We investigated the impact of visual states on basal ganglia oscillatory biomarkers, comparing local field potentials (LFPs) dynamics between Parkinson’s disease (PD) and dystonia and developing a decoding model for state identification. Simultaneous LFPs recordings from the subthalamic nucleus (STN) or globus pallidus internus (GPi), and cortex were obtained from 18 PD and 18 dystonia patients. In the eyes-closed state, theta and alpha power increased in the basal ganglia, with stronger coherence to the central cortex, more pronounced in the STN than in the GPi. Machine learning models identified the eyes-closed state with 88% accuracy for STN and 77% for GPi. The sensorimotor STN and GPi were most informative. The present findings provide proof-of-concept that basal ganglia LFPs can reliably predict a physiological state, highlighting the potential influence of physiological oscillatory activity on pathological bands and its relevance for adaptive stimulation paradigms.
{"title":"Decoding the impact of visual states on adaptive deep brain stimulation feedback signals in movement disorders","authors":"Guan-Yu Zhu, Timon Merk, Konstantin Butenko, Zi-Xiao Yin, Ying-Chuan Chen, Ning-Fei Li, Thomas Binns, Ruo-Yu Ma, Ting-Ting Du, Yu-Ye Liu, Hu-Tao Xie, Lin Shi, An-Chao Yang, Fan-Gang Meng, Andrea A. Kühn, Jian-Guo Zhang, Wolf-Julian Neumann","doi":"10.1038/s41531-026-01273-3","DOIUrl":"https://doi.org/10.1038/s41531-026-01273-3","url":null,"abstract":"We investigated the impact of visual states on basal ganglia oscillatory biomarkers, comparing local field potentials (LFPs) dynamics between Parkinson’s disease (PD) and dystonia and developing a decoding model for state identification. Simultaneous LFPs recordings from the subthalamic nucleus (STN) or globus pallidus internus (GPi), and cortex were obtained from 18 PD and 18 dystonia patients. In the eyes-closed state, theta and alpha power increased in the basal ganglia, with stronger coherence to the central cortex, more pronounced in the STN than in the GPi. Machine learning models identified the eyes-closed state with 88% accuracy for STN and 77% for GPi. The sensorimotor STN and GPi were most informative. The present findings provide proof-of-concept that basal ganglia LFPs can reliably predict a physiological state, highlighting the potential influence of physiological oscillatory activity on pathological bands and its relevance for adaptive stimulation paradigms.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"86 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089881","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}
Pub Date : 2026-01-30DOI: 10.1038/s41531-026-01271-5
Sarah Jaehwa Park,Barış Erhan Özdinç,Kathryn Grace Coker,Dana M Walsh,Devon J Fox,Samantha Evans,Joshua Farahnik,Kelly Moffat,Margaret Boomgaarden,Laurie K Mischley
Previous studies suggest there are distinct gut microbial and functional variations in patients with Parkinson's disease (PwPD) that may reveal potential microbiome signatures or biomarkers to aid in early detection of the disease. In this case-control study, we used whole genome sequencing to compare the stool samples of 55 PwPD to 42 healthy controls (HC) from a public database (BioProject Accession PRJEB39223). For bacterial phyla, we observed a greater relative abundance in Firmicutes and Actinobacteria among PwPD, while that of Bacteroidetes was lower. For phages, PwPD had a greater relative abundance of Siphoviridae, Tectiviridae, and Podoviridae, while Microviridae was lower. Moreover, we described 10 functional pathways that most significantly differed between PwPD and HC (all P < 0.0001). In conclusion, significant differences were observed in gut bacteria, phages, and functional pathways between PwPD and HC that both support and conflict with previous case-control studies and warrant further validation.
{"title":"Metagenomics indicates an interplay of the microbiome and functional pathways in Parkinson's disease.","authors":"Sarah Jaehwa Park,Barış Erhan Özdinç,Kathryn Grace Coker,Dana M Walsh,Devon J Fox,Samantha Evans,Joshua Farahnik,Kelly Moffat,Margaret Boomgaarden,Laurie K Mischley","doi":"10.1038/s41531-026-01271-5","DOIUrl":"https://doi.org/10.1038/s41531-026-01271-5","url":null,"abstract":"Previous studies suggest there are distinct gut microbial and functional variations in patients with Parkinson's disease (PwPD) that may reveal potential microbiome signatures or biomarkers to aid in early detection of the disease. In this case-control study, we used whole genome sequencing to compare the stool samples of 55 PwPD to 42 healthy controls (HC) from a public database (BioProject Accession PRJEB39223). For bacterial phyla, we observed a greater relative abundance in Firmicutes and Actinobacteria among PwPD, while that of Bacteroidetes was lower. For phages, PwPD had a greater relative abundance of Siphoviridae, Tectiviridae, and Podoviridae, while Microviridae was lower. Moreover, we described 10 functional pathways that most significantly differed between PwPD and HC (all P < 0.0001). In conclusion, significant differences were observed in gut bacteria, phages, and functional pathways between PwPD and HC that both support and conflict with previous case-control studies and warrant further validation.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"282 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146088920","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}
Pub Date : 2026-01-29DOI: 10.1038/s41531-025-01243-1
G Issabekov,B Al-Fatly,M Mousavi,J Roediger,R Köhler,J Habets,A L de Almeida Marcelino,M S Tuncer,P Krause,M Astalosch,D Kübler-Weller,C Spies,P Spindler,K Faust,P Truckenmueller,G H Schneider,A A Kühn,L A Steiner
Propofol is widely used for general anesthesia (GA) during deep brain stimulation (DBS) surgery targeting the subthalamic nucleus (STN) in Parkinson's disease (PD), yet its effects on intraoperative spatial navigation, critical for electrode placement, remain contentious. We performed multimodal analysis on 583 microelectrode recordings (MER) from PD patients undergoing DBS surgery under local anesthesia (LA) and GA. Deep sedation interfered with the identification of the dorsal STN border, and propofol dosages >4 mg/kg/h resulted in deeper final electrodes. While firing rate (FR) and burst index (BI) differed between LA and GA, only BI distinguished imaging-defined STN and correlated negatively with the proximity to the DBS sweetspot across conditions. Thus, propofol-based GA complicates navigation in DBS surgery, but MER remain informative if propofol levels are carefully controlled. BI emerges as a potential biomarker when MER are "polluted" by high levels of propofol, offering critical feedback during DBS surgery under GA.
{"title":"The graded effect of propofol in electrophysiology-guided navigation during deep brain stimulation surgery.","authors":"G Issabekov,B Al-Fatly,M Mousavi,J Roediger,R Köhler,J Habets,A L de Almeida Marcelino,M S Tuncer,P Krause,M Astalosch,D Kübler-Weller,C Spies,P Spindler,K Faust,P Truckenmueller,G H Schneider,A A Kühn,L A Steiner","doi":"10.1038/s41531-025-01243-1","DOIUrl":"https://doi.org/10.1038/s41531-025-01243-1","url":null,"abstract":"Propofol is widely used for general anesthesia (GA) during deep brain stimulation (DBS) surgery targeting the subthalamic nucleus (STN) in Parkinson's disease (PD), yet its effects on intraoperative spatial navigation, critical for electrode placement, remain contentious. We performed multimodal analysis on 583 microelectrode recordings (MER) from PD patients undergoing DBS surgery under local anesthesia (LA) and GA. Deep sedation interfered with the identification of the dorsal STN border, and propofol dosages >4 mg/kg/h resulted in deeper final electrodes. While firing rate (FR) and burst index (BI) differed between LA and GA, only BI distinguished imaging-defined STN and correlated negatively with the proximity to the DBS sweetspot across conditions. Thus, propofol-based GA complicates navigation in DBS surgery, but MER remain informative if propofol levels are carefully controlled. BI emerges as a potential biomarker when MER are \"polluted\" by high levels of propofol, offering critical feedback during DBS surgery under GA.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"82 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073335","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}
Neuronal mitochondria display distinct morphologies across compartments, with dendritic mitochondria being elongated and axonal ones shorter, and their morphologies are dynamically changed via fusion and fission machineries. Mitochondrial structural abnormalities are common in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, yet systematic evaluation of therapeutic targets remains limited. Here, we tested key mitochondrial shape regulators, mitofusin 1/2 for fusion and Mff/Fis1 for fission, in an α-synucleinopathy model. Using MitoVis, a deep learning-based neuronal mitochondrial image analysis tool, we achieved rapid, compartment-specific analysis of mitochondrial morphologies. Among all interventions, Fis1 knockdown most effectively protected mitochondrial structure to control levels without inducing over-elongation of axonal mitochondria, which was linked to abnormal Ca2+ dynamics. While all manipulations preserved dendritic spine loss, Fis1 optimally maintained axonal mitochondrial function. These findings demonstrate a high-throughput screening approach for mitochondrial regulators and highlight Fis1 as a promising preventive/therapeutic target. Our results support targeting mitochondrial morphology as a viable strategy for treating α-synucleinopathy and potentially other mitochondria-related neurodegenerative diseases.
{"title":"Systematic evaluation of mitochondrial morphology regulators for amelioration of neuronal α-synucleinopathy.","authors":"Su Yeon Kim,JunYoung Choi,Dong Cheol Jang,Pa Reum Lee,Gyu-Sang Hong,Jinkuk Kim,Won-Ki Jeong,Kihoon Han,Seok-Kyu Kwon","doi":"10.1038/s41531-026-01277-z","DOIUrl":"https://doi.org/10.1038/s41531-026-01277-z","url":null,"abstract":"Neuronal mitochondria display distinct morphologies across compartments, with dendritic mitochondria being elongated and axonal ones shorter, and their morphologies are dynamically changed via fusion and fission machineries. Mitochondrial structural abnormalities are common in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, yet systematic evaluation of therapeutic targets remains limited. Here, we tested key mitochondrial shape regulators, mitofusin 1/2 for fusion and Mff/Fis1 for fission, in an α-synucleinopathy model. Using MitoVis, a deep learning-based neuronal mitochondrial image analysis tool, we achieved rapid, compartment-specific analysis of mitochondrial morphologies. Among all interventions, Fis1 knockdown most effectively protected mitochondrial structure to control levels without inducing over-elongation of axonal mitochondria, which was linked to abnormal Ca2+ dynamics. While all manipulations preserved dendritic spine loss, Fis1 optimally maintained axonal mitochondrial function. These findings demonstrate a high-throughput screening approach for mitochondrial regulators and highlight Fis1 as a promising preventive/therapeutic target. Our results support targeting mitochondrial morphology as a viable strategy for treating α-synucleinopathy and potentially other mitochondria-related neurodegenerative diseases.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"4 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056513","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}
Pub Date : 2026-01-27DOI: 10.1038/s41531-025-01236-0
Joshua D Elford,Elise J Heesbeen,Nienke A van der Plaats,Johan Garssen,Aletta D Kraneveld,Lucianne Groenink,Paula Perez Pardo
The gut microbiome is believed to play an important role in the development and onset of Parkinson's disease (PD). While human studies report differences in gut microbiota between PD individuals and healthy controls, it is unclear whether preclinical animal models show similar patterns. We performed a systematic review and Bayesian regularised meta-analysis of preclinical PD studies that assessed both motor function and gut microbiota. Motor deficits were consistently observed across models, but gut bacterial diversity (α-diversity) and changes in key taxa (e.g. Akkermansia, Lactobacillus, Bifidobacterium) were inconsistent and poorly aligned with human data. In contrast, short-chain fatty acids (SCFAs) showed more reproducible changes and greater translatability to human findings. Chronic toxin-based models demonstrated the highest reproducibility. Overall, gut microbiota composition in animal PD models lacks consistency and human relevance, whereas SCFAs may offer a more reliable outcome. Finally, our study makes possible recommendations for reporting to improve future studies.
{"title":"Gut bacteria composition in animal models of Parkinson's disease: a systematic review and meta-analysis.","authors":"Joshua D Elford,Elise J Heesbeen,Nienke A van der Plaats,Johan Garssen,Aletta D Kraneveld,Lucianne Groenink,Paula Perez Pardo","doi":"10.1038/s41531-025-01236-0","DOIUrl":"https://doi.org/10.1038/s41531-025-01236-0","url":null,"abstract":"The gut microbiome is believed to play an important role in the development and onset of Parkinson's disease (PD). While human studies report differences in gut microbiota between PD individuals and healthy controls, it is unclear whether preclinical animal models show similar patterns. We performed a systematic review and Bayesian regularised meta-analysis of preclinical PD studies that assessed both motor function and gut microbiota. Motor deficits were consistently observed across models, but gut bacterial diversity (α-diversity) and changes in key taxa (e.g. Akkermansia, Lactobacillus, Bifidobacterium) were inconsistent and poorly aligned with human data. In contrast, short-chain fatty acids (SCFAs) showed more reproducible changes and greater translatability to human findings. Chronic toxin-based models demonstrated the highest reproducibility. Overall, gut microbiota composition in animal PD models lacks consistency and human relevance, whereas SCFAs may offer a more reliable outcome. Finally, our study makes possible recommendations for reporting to improve future studies.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"51 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056499","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}
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