Pub Date : 2026-01-22DOI: 10.1038/s41531-026-01264-4
Kara A Johnson,Patricia B Coutinho,Lauren E Kenney,Joshua K Wong,Justin D Hilliard,Kelly D Foote,Dawn Bowers,Gregory M Pontone,Coralie de Hemptinne
Depression is increasingly recognized as a prevalent source of disability in individuals with Parkinson's disease (PD), but its pathophysiology is not well understood. Neural activity in the basal ganglia, particularly the subthalamic nucleus, has been linked to depression in PD, but the role of the pallidum remains unclear. This retrospective study aimed to correlate preoperative depression symptoms with intraoperative resting-state neural activity recorded from the pallidum in N = 50 patients who underwent deep-brain stimulation (DBS) implantation surgery. Patients with clinically elevated depression symptoms exhibited elevated beta (13-30 Hz) power compared to patients without depression. Beta power, particularly high beta (20-30 Hz) power, was also associated with depression symptom severity, even when controlling for other demographic, clinical, pharmacological, and neurophysiological variables. These results suggest pallidal beta power as a potential biomarker of depression in PD and set the stage for tailoring DBS therapy to improve psychiatric symptoms in PD.
{"title":"Pallidal beta power is associated with depression in Parkinson's disease.","authors":"Kara A Johnson,Patricia B Coutinho,Lauren E Kenney,Joshua K Wong,Justin D Hilliard,Kelly D Foote,Dawn Bowers,Gregory M Pontone,Coralie de Hemptinne","doi":"10.1038/s41531-026-01264-4","DOIUrl":"https://doi.org/10.1038/s41531-026-01264-4","url":null,"abstract":"Depression is increasingly recognized as a prevalent source of disability in individuals with Parkinson's disease (PD), but its pathophysiology is not well understood. Neural activity in the basal ganglia, particularly the subthalamic nucleus, has been linked to depression in PD, but the role of the pallidum remains unclear. This retrospective study aimed to correlate preoperative depression symptoms with intraoperative resting-state neural activity recorded from the pallidum in N = 50 patients who underwent deep-brain stimulation (DBS) implantation surgery. Patients with clinically elevated depression symptoms exhibited elevated beta (13-30 Hz) power compared to patients without depression. Beta power, particularly high beta (20-30 Hz) power, was also associated with depression symptom severity, even when controlling for other demographic, clinical, pharmacological, and neurophysiological variables. These results suggest pallidal beta power as a potential biomarker of depression in PD and set the stage for tailoring DBS therapy to improve psychiatric symptoms in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"52 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021552","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}
Parkinson's disease (PD) is a neurodegenerative disorder with complex motor and non-motor symptoms. This network meta-analysis evaluated the combined effects of medication and 20 rehabilitation therapies on motor function, neuro-psychiatric health, and quality of life in 8202 PD patients across 186 randomized controlled trials. Traditional Chinese Rehabilitation Therapy (TCRT), Exoskeleton-Assisted Rehabilitation Therapy (EART), Hydrotherapy Rehabilitation Therapy (HRT), and Conventional Kinesitherapy (CKT) significantly improved balance, while Mind-Body Exercise Therapy (MBET) and Non-Invasive Brain Stimulation Therapy (NIBST) enhanced overall motor capacity and reduced freezing of gait (FOG). Resistance Training Rehabilitation Therapy (RTRT) and Non-Invasive Brain Stimulation Therapy (NIBST) improved cognitive function, and Mind-Body Exercise Therapy (MBET) alleviated negative mood. Upper Limb Rehabilitation Therapy (ULRT) and Resistance Training Rehabilitation Therapy (RTRT) showed notable quality-of-life benefits. However, confidence in outcomes was often low due to risk of bias and imprecision. Meta-regression indicated that intervention duration was negatively correlated with cognitive gains. These findings highlight the need for precise, integrated rehabilitation strategies targeting specific symptoms to optimize PD management. Future research should explore individualized, mechanism-driven approaches to advance precision rehabilitation.
{"title":"Comparative effects of medication combined with twenty rehabilitation therapies: core outcomes in 8202 parkinson's patients.","authors":"Haojie Li,Xinyu Lin,Rui Huang,Shangjun Huang,Xie Wu","doi":"10.1038/s41531-026-01266-2","DOIUrl":"https://doi.org/10.1038/s41531-026-01266-2","url":null,"abstract":"Parkinson's disease (PD) is a neurodegenerative disorder with complex motor and non-motor symptoms. This network meta-analysis evaluated the combined effects of medication and 20 rehabilitation therapies on motor function, neuro-psychiatric health, and quality of life in 8202 PD patients across 186 randomized controlled trials. Traditional Chinese Rehabilitation Therapy (TCRT), Exoskeleton-Assisted Rehabilitation Therapy (EART), Hydrotherapy Rehabilitation Therapy (HRT), and Conventional Kinesitherapy (CKT) significantly improved balance, while Mind-Body Exercise Therapy (MBET) and Non-Invasive Brain Stimulation Therapy (NIBST) enhanced overall motor capacity and reduced freezing of gait (FOG). Resistance Training Rehabilitation Therapy (RTRT) and Non-Invasive Brain Stimulation Therapy (NIBST) improved cognitive function, and Mind-Body Exercise Therapy (MBET) alleviated negative mood. Upper Limb Rehabilitation Therapy (ULRT) and Resistance Training Rehabilitation Therapy (RTRT) showed notable quality-of-life benefits. However, confidence in outcomes was often low due to risk of bias and imprecision. Meta-regression indicated that intervention duration was negatively correlated with cognitive gains. These findings highlight the need for precise, integrated rehabilitation strategies targeting specific symptoms to optimize PD management. Future research should explore individualized, mechanism-driven approaches to advance precision rehabilitation.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"32 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021300","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 : 2026-01-22DOI: 10.1038/s41531-025-01240-4
Josefine Waldthaler, Igori Comarovschii, Daniel Lundqvist
Motor dysfunction in Parkinson's disease (PD) has been linked to widespread oscillatory changes within the basal ganglia-thalamic-cortical network, particularly in the beta frequency range. However, the evolution of cortical neurophysiological alterations and their relationship to clinical progression remain poorly understood. We conducted a longitudinal resting-state magnetoencephalography (MEG) study in 27 persons with PD and 30 healthy individuals with a mean follow-up time of 4 years. Source-reconstructed MEG data were parcellated into cortical regions, from which power spectra were parameterized to separate oscillatory peaks from the aperiodic component. An increase in the aperiodic exponent in the left postcentral region was associated with progression of rigidity. Peak beta power in parieto-temporo-occipital regions was elevated at baseline, correlating with less severe bradykinesia. This negative relationship weakened over time in patients with progressive symptoms, suggesting an association with compensatory mechanisms. Using partial least squares regression to predict future disease course from baseline neurophysiological features, 19.5% of the variability in motor progression was explained in an independent validation cohort. Our results emphasize the importance of separating aperiodic neural activity from periodic oscillations as a progressive alteration of the aperiodic component represented the most prominent PD-related neurophysiological change. Further, our findings highlight the potential predictive value of resting-state neurophysiology for future disease progression.
{"title":"Magnetoencephalography-based prediction of longitudinal symptom progression in Parkinson's disease.","authors":"Josefine Waldthaler, Igori Comarovschii, Daniel Lundqvist","doi":"10.1038/s41531-025-01240-4","DOIUrl":"10.1038/s41531-025-01240-4","url":null,"abstract":"<p><p>Motor dysfunction in Parkinson's disease (PD) has been linked to widespread oscillatory changes within the basal ganglia-thalamic-cortical network, particularly in the beta frequency range. However, the evolution of cortical neurophysiological alterations and their relationship to clinical progression remain poorly understood. We conducted a longitudinal resting-state magnetoencephalography (MEG) study in 27 persons with PD and 30 healthy individuals with a mean follow-up time of 4 years. Source-reconstructed MEG data were parcellated into cortical regions, from which power spectra were parameterized to separate oscillatory peaks from the aperiodic component. An increase in the aperiodic exponent in the left postcentral region was associated with progression of rigidity. Peak beta power in parieto-temporo-occipital regions was elevated at baseline, correlating with less severe bradykinesia. This negative relationship weakened over time in patients with progressive symptoms, suggesting an association with compensatory mechanisms. Using partial least squares regression to predict future disease course from baseline neurophysiological features, 19.5% of the variability in motor progression was explained in an independent validation cohort. Our results emphasize the importance of separating aperiodic neural activity from periodic oscillations as a progressive alteration of the aperiodic component represented the most prominent PD-related neurophysiological change. Further, our findings highlight the potential predictive value of resting-state neurophysiology for future disease progression.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":" ","pages":"29"},"PeriodicalIF":8.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12847951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030452","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}
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of α-synuclein aggregates. Ceramide metabolism is increasingly implicated in protein aggregation and mitochondrial dysfunction, both of which are prevalent in neurodegenerative disorders. While prior studies using cell lines have hinted at ceramide's role in PD, the in vivo relevance and therapeutic efficacy of inhibiting its synthesis remained largely unexplored. We aimed to evaluate the therapeutic potential of inhibiting ceramide synthesis in various models of PD, including the A53T α-synuclein transgenic mouse model, primary neurons from patients with PD, and patient-derived midbrain organoids. We found that inhibiting de novo ceramide biosynthesis decreases α-synuclein aggregation and improves motor and cognitive function in A53T α-synuclein transgenic mice. Treatment with myriocin, a serine palmitoyltransferase inhibitor, restored mitochondrial morphology, enhanced mitophagy, and reduced neuroinflammation. Single-nucleus transcriptomic analysis revealed that myriocin normalized gene networks related to synaptic transmission, mitochondrial homeostasis, and inflammation. Additionally, human midbrain organoids derived from PD patient-induced pluripotent stem cells exhibited reduced α-synuclein aggregation and preserved dopaminergic neurons following myriocin treatment. Together, these results suggest that targeting ceramide synthesis is a promising strategy for addressing protein aggregation and neuronal death in PD.
{"title":"Inhibition of de novo ceramide synthesis mitigates alpha-synuclein pathology in a Parkinson's disease mouse model.","authors":"Eunkyung Lee,Moon-Young Park,Minkuk Park,Na-Yeong Kim,Shibo Wei,Nahee Hwang,Dongryeol Ryu,Hoon Ryu,Dohyun Park,Gakyung Lee,Chang-Myung Oh","doi":"10.1038/s41531-026-01263-5","DOIUrl":"https://doi.org/10.1038/s41531-026-01263-5","url":null,"abstract":"Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of α-synuclein aggregates. Ceramide metabolism is increasingly implicated in protein aggregation and mitochondrial dysfunction, both of which are prevalent in neurodegenerative disorders. While prior studies using cell lines have hinted at ceramide's role in PD, the in vivo relevance and therapeutic efficacy of inhibiting its synthesis remained largely unexplored. We aimed to evaluate the therapeutic potential of inhibiting ceramide synthesis in various models of PD, including the A53T α-synuclein transgenic mouse model, primary neurons from patients with PD, and patient-derived midbrain organoids. We found that inhibiting de novo ceramide biosynthesis decreases α-synuclein aggregation and improves motor and cognitive function in A53T α-synuclein transgenic mice. Treatment with myriocin, a serine palmitoyltransferase inhibitor, restored mitochondrial morphology, enhanced mitophagy, and reduced neuroinflammation. Single-nucleus transcriptomic analysis revealed that myriocin normalized gene networks related to synaptic transmission, mitochondrial homeostasis, and inflammation. Additionally, human midbrain organoids derived from PD patient-induced pluripotent stem cells exhibited reduced α-synuclein aggregation and preserved dopaminergic neurons following myriocin treatment. Together, these results suggest that targeting ceramide synthesis is a promising strategy for addressing protein aggregation and neuronal death in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"16 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005227","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 : 2026-01-21DOI: 10.1038/s41531-026-01267-1
Iro Boura,Shaimaa Sait,Nikolaos M Marinakis,Kumar Arvind,Ruth Chia,Anindita Ray,Giannis Vatsellas,Theodoros Loupis,Vasiliki Pavlaki,Periklis Makrythanasis,Panayiotis Mitsias,Georgia Xiromerisiou,Sonja W Scholz,Cleanthe Spanaki
{"title":"Author Correction: The genetic architecture of Parkinson's disease on the Island of Crete.","authors":"Iro Boura,Shaimaa Sait,Nikolaos M Marinakis,Kumar Arvind,Ruth Chia,Anindita Ray,Giannis Vatsellas,Theodoros Loupis,Vasiliki Pavlaki,Periklis Makrythanasis,Panayiotis Mitsias,Georgia Xiromerisiou,Sonja W Scholz,Cleanthe Spanaki","doi":"10.1038/s41531-026-01267-1","DOIUrl":"https://doi.org/10.1038/s41531-026-01267-1","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"116 1","pages":"22"},"PeriodicalIF":8.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015159","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 : 2026-01-21DOI: 10.1038/s41531-025-01256-w
Bharadwaj Nandakumar, Ajay K. Verma, Ying Yu, Ethan Marshall, Adele L. DeNicola, Jing Wang, Colum D. MacKinnon, Michael J. Howell, Jerrold L. Vitek, Luke A. Johnson
Reduction in neuronal firing from wake to sleep, i.e., sleep firing rate homeostasis (sFRH), is essential for restorative sleep. Sleep dysfunction is common in Parkinson’s disease (PD), but sFRH has not been investigated. Here, using a within-subject design in the nonhuman primate model of PD, we report that thalamocortical sFRH is disrupted in parkinsonism. These findings can inform therapeutic approaches tailored to normalize sFRH and reestablish restorative sleep in PD.
{"title":"Sleep firing rate homeostasis is disrupted in mild parkinsonism","authors":"Bharadwaj Nandakumar, Ajay K. Verma, Ying Yu, Ethan Marshall, Adele L. DeNicola, Jing Wang, Colum D. MacKinnon, Michael J. Howell, Jerrold L. Vitek, Luke A. Johnson","doi":"10.1038/s41531-025-01256-w","DOIUrl":"https://doi.org/10.1038/s41531-025-01256-w","url":null,"abstract":"Reduction in neuronal firing from wake to sleep, i.e., sleep firing rate homeostasis (sFRH), is essential for restorative sleep. Sleep dysfunction is common in Parkinson’s disease (PD), but sFRH has not been investigated. Here, using a within-subject design in the nonhuman primate model of PD, we report that thalamocortical sFRH is disrupted in parkinsonism. These findings can inform therapeutic approaches tailored to normalize sFRH and reestablish restorative sleep in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"6 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005965","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 : 2026-01-21DOI: 10.1038/s41531-026-01268-0
Qing-Qing Duan, Wei-Ming Su, Kang-Fu Yin, Sheng-Yi He, Ru-Yin Liu, Xiang-Jin Wen, Xiao-Jing Gu, Ting Chen, Bei Cao, Yong-Ping Chen
Accelerated biological aging serves as a risk factor for age-related diseases, its role in the prognosis of PD remains ambiguous. This study investigates the association between biological aging and the mortality in PD patients. Data were sourced from the UK Biobank. Independent prognostic factors for mortality in PD patients were assessed by Cox regression model, and a nomogram was developed to predict the survival of PD patients. A total of 569 PD patients were enrolled in this study. Phenotypic age (PhenoAge) and PhenoAge acceleration (PhenoAgeAccel) were found to affect the survival in PD patients. Independent risk factors for PD mortality included age, male gender, smoke, underweight, depressive mood, low-density lipoprotein, and higher genetic susceptibility. The nomogram constructed based on PhenoAge showed robust prediction performance for mortality in PD patients. PhenoAge emerges as a pivotal PD mortality predictor, enabling the identification of individuals experiencing accelerated biological aging and implementing targeted interventions.
{"title":"Biological aging predicts mortality in Parkinson’s patients: evidence from UK Biobank","authors":"Qing-Qing Duan, Wei-Ming Su, Kang-Fu Yin, Sheng-Yi He, Ru-Yin Liu, Xiang-Jin Wen, Xiao-Jing Gu, Ting Chen, Bei Cao, Yong-Ping Chen","doi":"10.1038/s41531-026-01268-0","DOIUrl":"https://doi.org/10.1038/s41531-026-01268-0","url":null,"abstract":"Accelerated biological aging serves as a risk factor for age-related diseases, its role in the prognosis of PD remains ambiguous. This study investigates the association between biological aging and the mortality in PD patients. Data were sourced from the UK Biobank. Independent prognostic factors for mortality in PD patients were assessed by Cox regression model, and a nomogram was developed to predict the survival of PD patients. A total of 569 PD patients were enrolled in this study. Phenotypic age (PhenoAge) and PhenoAge acceleration (PhenoAgeAccel) were found to affect the survival in PD patients. Independent risk factors for PD mortality included age, male gender, smoke, underweight, depressive mood, low-density lipoprotein, and higher genetic susceptibility. The nomogram constructed based on PhenoAge showed robust prediction performance for mortality in PD patients. PhenoAge emerges as a pivotal PD mortality predictor, enabling the identification of individuals experiencing accelerated biological aging and implementing targeted interventions.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"184 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005966","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 : 2026-01-16DOI: 10.1038/s41531-025-01239-x
M Y Schmidt,A M Cuervo,K L Double,D Ehninger,M S Goldberg,K Harvey,J H J Hoeijmakers,K C Luk,P G Mastroberardino,D J Moore,L J Niedernhofer,L É Trudeau,D Jurk,J K Andersen,I Bellantuono
Aging is the most significant risk factor for Parkinson's disease (PD), yet its role remains underexplored. The International Network for Parkinson's Disease Modelling and Aging (PD-AGE), funded by the Michael J. Fox Foundation, was established to address these challenges. Through collaborative efforts, the PD-AGE mouse-model working group developed a roadmap to prioritize mouse models, reach consensus on experimental approaches, and standardize protocols to investigate the intersection of aging and PD.
衰老是帕金森病（PD）最重要的危险因素，但其作用仍未得到充分探讨。由Michael J. Fox基金会资助的国际帕金森病建模与衰老网络（PD-AGE）就是为了应对这些挑战而建立的。通过合作，PD- age小鼠模型工作组制定了一个路线图，以确定小鼠模型的优先级，在实验方法上达成共识，并标准化协议，以研究衰老与PD的交集。
{"title":"Unraveling the intersection of aging and Parkinson's disease: a collaborative roadmap for advancing research models.","authors":"M Y Schmidt,A M Cuervo,K L Double,D Ehninger,M S Goldberg,K Harvey,J H J Hoeijmakers,K C Luk,P G Mastroberardino,D J Moore,L J Niedernhofer,L É Trudeau,D Jurk,J K Andersen,I Bellantuono","doi":"10.1038/s41531-025-01239-x","DOIUrl":"https://doi.org/10.1038/s41531-025-01239-x","url":null,"abstract":"Aging is the most significant risk factor for Parkinson's disease (PD), yet its role remains underexplored. The International Network for Parkinson's Disease Modelling and Aging (PD-AGE), funded by the Michael J. Fox Foundation, was established to address these challenges. Through collaborative efforts, the PD-AGE mouse-model working group developed a roadmap to prioritize mouse models, reach consensus on experimental approaches, and standardize protocols to investigate the intersection of aging and PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"56 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986573","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 : 2026-01-16DOI: 10.1038/s41531-025-01199-2
MacKenzie L Bolen,Marc Buendia,Ji Shi,Hannah Staley,Jennifer M Kachergus,Philip A Efron,Gwoncheol Park,Ravinder Nagpal,Stephan D Alvarez,Qing-Shan Xue,Nikolaus R McFarland,Ellen M Zimmermann,Christopher E Forsmark,Kelly B Menees,Azucena Salas,E Aubrey Thompson,Malú Gámez Tansey
Parkinson's disease (PD) is the fastest-growing neurodegenerative disease in the world1. Gastrointestinal (GI) dysfunction can occur decades before motor impairments and in up to 80% of individuals living with PD2-4. We investigated peripheral relationships that may underlie mechanisms along the gut-blood axis that contribute to PD progression. Single-cell multiomic spatial molecular imaging (SMI) of colonic tissue localized and identified inflammatory injury within epithelial cells that appear to be associated with iron mishandling in both inflammatory bowel disease (IBD) and PD biosamples. We found that both the single-cell SMI of RNA and protein revealed parallel cross-modal dysregulation in the gut epithelium, in both IBD and PD biosamples. These data are accompanied by plasma (PD) and stool (IBD) protein depletion of CCL22. Our findings suggest iron mishandling along the gut barrier likely contributes to systemic inflammation, which may be one catalyst that primes circulating immune cells to body-first PD progression.
{"title":"Spatial single-cell multiomics reveals peripheral immune dysfunction in Parkinson's and inflammatory bowel disease.","authors":"MacKenzie L Bolen,Marc Buendia,Ji Shi,Hannah Staley,Jennifer M Kachergus,Philip A Efron,Gwoncheol Park,Ravinder Nagpal,Stephan D Alvarez,Qing-Shan Xue,Nikolaus R McFarland,Ellen M Zimmermann,Christopher E Forsmark,Kelly B Menees,Azucena Salas,E Aubrey Thompson,Malú Gámez Tansey","doi":"10.1038/s41531-025-01199-2","DOIUrl":"https://doi.org/10.1038/s41531-025-01199-2","url":null,"abstract":"Parkinson's disease (PD) is the fastest-growing neurodegenerative disease in the world1. Gastrointestinal (GI) dysfunction can occur decades before motor impairments and in up to 80% of individuals living with PD2-4. We investigated peripheral relationships that may underlie mechanisms along the gut-blood axis that contribute to PD progression. Single-cell multiomic spatial molecular imaging (SMI) of colonic tissue localized and identified inflammatory injury within epithelial cells that appear to be associated with iron mishandling in both inflammatory bowel disease (IBD) and PD biosamples. We found that both the single-cell SMI of RNA and protein revealed parallel cross-modal dysregulation in the gut epithelium, in both IBD and PD biosamples. These data are accompanied by plasma (PD) and stool (IBD) protein depletion of CCL22. Our findings suggest iron mishandling along the gut barrier likely contributes to systemic inflammation, which may be one catalyst that primes circulating immune cells to body-first PD progression.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"30 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986574","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 : 2026-01-16DOI: 10.1038/s41531-025-01246-y
Liam Horan-Portelance,Michiyo Iba,Dominic J Acri,J Raphael Gibbs,Mark R Cookson
In Parkinson's disease and dementia with Lewy bodies, aggregated and phosphorylated α-synuclein appears in select neurons throughout cortical and subcortical regions, but little is currently known about why certain populations are selectively vulnerable. Here, using imaging spatial transcriptomics (IST) coupled with downstream immunofluorescence for α-synuclein phosphorylated at Ser129 (pSyn) in the same tissue sections, we identified neuronal subtypes in the cortex and hippocampus of transgenic human α-synuclein-overexpressing mice that preferentially developed pSyn accumulation. Additionally, we investigated the transcriptional underpinnings of this vulnerability, pointing to expression of Plk2, which phosphorylates α-synuclein at Ser129, and human SNCA (hSNCA), as key to pSyn development. Finally, we performed differential expression analysis, revealing gene expression changes broadly downstream of hSNCA overexpression, as well as pSyn-dependent alterations in mitochondrial and endolysosomal genes. Overall, this study yields new insights into the formation of phospho-α-synuclein and its downstream effects in a synucleinopathy mouse model.
{"title":"Imaging spatial transcriptomics reveals molecular patterns underlying accumulation of p-Ser129 α-synuclein in a transgenic mouse model.","authors":"Liam Horan-Portelance,Michiyo Iba,Dominic J Acri,J Raphael Gibbs,Mark R Cookson","doi":"10.1038/s41531-025-01246-y","DOIUrl":"https://doi.org/10.1038/s41531-025-01246-y","url":null,"abstract":"In Parkinson's disease and dementia with Lewy bodies, aggregated and phosphorylated α-synuclein appears in select neurons throughout cortical and subcortical regions, but little is currently known about why certain populations are selectively vulnerable. Here, using imaging spatial transcriptomics (IST) coupled with downstream immunofluorescence for α-synuclein phosphorylated at Ser129 (pSyn) in the same tissue sections, we identified neuronal subtypes in the cortex and hippocampus of transgenic human α-synuclein-overexpressing mice that preferentially developed pSyn accumulation. Additionally, we investigated the transcriptional underpinnings of this vulnerability, pointing to expression of Plk2, which phosphorylates α-synuclein at Ser129, and human SNCA (hSNCA), as key to pSyn development. Finally, we performed differential expression analysis, revealing gene expression changes broadly downstream of hSNCA overexpression, as well as pSyn-dependent alterations in mitochondrial and endolysosomal genes. Overall, this study yields new insights into the formation of phospho-α-synuclein and its downstream effects in a synucleinopathy mouse model.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"58 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986571","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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