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}
Pub Date : 2026-01-16DOI: 10.1038/s41531-025-01249-9
P V Casanova, I Freitag-Berenguel, E Saavedra-López, M Usandizaga-Estarloa, C Ríos-Cuadrado, P Martínez-Remedios, C Giménez-Montes, E Clinton, M Roig-Martínez, G P Cribaro, C Barcia
It is postulated that microglial cells interact with dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc), playing a critical role in Parkinson's disease (PD) neurodegeneration. However, the specific mechanisms by which microglial reactivity is triggered remain unclear. Experimental models of PD in mice indicate that phagocytosis drives the elimination of degenerating neurons, suggesting that blocking this microglial function could preserve remaining DA neurons. Here, we pinpoint the role of Fcγ receptor (FcγR) as a potential trigger of microglial phagocytosis in PD. We found that FcγR is overexpressed in the SNpc of PD patients, alongside indications of phagocytic microglia. Likewise, experimental models of PD show equivalent results. Importantly, blocking FcγR in vivo and in vitro, with neutralizing antibodies, reduced the microglial-mediated elimination of DA cells. These results highlight FcγR as a critical factor inducing DA neuron phagocytosis in PD and suggest a novel immunotherapeutic strategy to prevent neuronal loss.
{"title":"Microglial low-affinity FcγR mediates the phagocytic elimination of dopaminergic neurons in Parkinson's disease degeneration.","authors":"P V Casanova, I Freitag-Berenguel, E Saavedra-López, M Usandizaga-Estarloa, C Ríos-Cuadrado, P Martínez-Remedios, C Giménez-Montes, E Clinton, M Roig-Martínez, G P Cribaro, C Barcia","doi":"10.1038/s41531-025-01249-9","DOIUrl":"10.1038/s41531-025-01249-9","url":null,"abstract":"<p><p>It is postulated that microglial cells interact with dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc), playing a critical role in Parkinson's disease (PD) neurodegeneration. However, the specific mechanisms by which microglial reactivity is triggered remain unclear. Experimental models of PD in mice indicate that phagocytosis drives the elimination of degenerating neurons, suggesting that blocking this microglial function could preserve remaining DA neurons. Here, we pinpoint the role of Fcγ receptor (FcγR) as a potential trigger of microglial phagocytosis in PD. We found that FcγR is overexpressed in the SNpc of PD patients, alongside indications of phagocytic microglia. Likewise, experimental models of PD show equivalent results. Importantly, blocking FcγR in vivo and in vitro, with neutralizing antibodies, reduced the microglial-mediated elimination of DA cells. These results highlight FcγR as a critical factor inducing DA neuron phagocytosis in PD and suggest a novel immunotherapeutic strategy to prevent neuronal loss.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":" ","pages":"35"},"PeriodicalIF":8.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990236","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}
Pub Date : 2026-01-15DOI: 10.1038/s41531-025-01250-2
Ting Zhang, Yuwen Wang
Cuproptosis has been linked to Parkinson’s disease (PD), but underlying genetic mechanisms remain unclear. We integrated multi-omic QTL data (methylation, gene expression, protein) with GWAS data of PD (discovery: GWAS Catalog; replication: UK Biobank/FinnGen/IEU). Integrated summary-data Mendelian randomization (SMR) with colocalization analyses revealed regulatory relationships involving 4 candidate genes (ISCA1, PDE6B, PTGES, and CERS2). Replication analyses demonstrated consistent CERS2/PDE6B methylation effects across cohorts. Experimental validation in MPTP-treated mice demonstrated that the copper chelator tetrathiomolybdate (TTM) robustly rescued motor deficits and prevented dopaminergic neurodegeneration. Mechanistically, TTM reversed core features of cuproptosis, including striatal copper accumulation and the destabilization of lipoylated TCA cycle proteins. TTM also normalized the expression of all four candidate genes, confirming a copper-dependent regulatory axis predicted by our SMR analysis. This study provides a functional link between cuproptosis-related genes and PD pathogenesis, highlighting copper dyshomeostasis as a key pathogenic driver and a potential therapeutic target.
{"title":"Multi-omic insight into the molecular mechanism of cuproptosis-related genes in the pathogenesis of Parkinson’s disease","authors":"Ting Zhang, Yuwen Wang","doi":"10.1038/s41531-025-01250-2","DOIUrl":"https://doi.org/10.1038/s41531-025-01250-2","url":null,"abstract":"Cuproptosis has been linked to Parkinson’s disease (PD), but underlying genetic mechanisms remain unclear. We integrated multi-omic QTL data (methylation, gene expression, protein) with GWAS data of PD (discovery: GWAS Catalog; replication: UK Biobank/FinnGen/IEU). Integrated summary-data Mendelian randomization (SMR) with colocalization analyses revealed regulatory relationships involving 4 candidate genes (ISCA1, PDE6B, PTGES, and CERS2). Replication analyses demonstrated consistent CERS2/PDE6B methylation effects across cohorts. Experimental validation in MPTP-treated mice demonstrated that the copper chelator tetrathiomolybdate (TTM) robustly rescued motor deficits and prevented dopaminergic neurodegeneration. Mechanistically, TTM reversed core features of cuproptosis, including striatal copper accumulation and the destabilization of lipoylated TCA cycle proteins. TTM also normalized the expression of all four candidate genes, confirming a copper-dependent regulatory axis predicted by our SMR analysis. This study provides a functional link between cuproptosis-related genes and PD pathogenesis, highlighting copper dyshomeostasis as a key pathogenic driver and a potential therapeutic target.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"29 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968734","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 : 2026-01-15DOI: 10.1038/s41531-025-01233-3
Elena Bernasconi, Alberto Averna, Valentina D’Onofrio, Deborah Amstutz, Damian M. Herz, Laura Alva, Andreia D. Magalhães, Katrin Petermann, Ines Debove, M. Lenard Lachenmayer, Andreas Nowacki, Claudio Pollo, Paul Krack, Mario Sousa, Gerd Tinkhauser
Sensing-guided deep brain stimulation (DBS) offers potential to further optimize symptom control in Parkinson’s disease (PD) patients. Emerging evidence suggests that basal ganglia signals reflect not only motor, but also chronic neuropsychiatric symptoms. However, it remains unclear whether local field potentials (LFPs) can inform about acute neuropsychiatric states in PD, which we address in this work. Fourteen PD patients implanted with a brain-sense-enabled neurostimulator underwent an acute levodopa challenge OFF/ON stimulation one year after surgery. In each condition, resting state STN-LFPs were recorded, and the acute neuropsychiatric state was evaluated using the Neuropsychiatric Fluctuation Scale. The relationship between neuropsychiatric state and fluctuation scores with STN low-frequency activity (4–12 Hz) was assessed. An acute low neuropsychiatric state in the OFF-medication condition was associated with elevated theta/low-alpha power. Moreover, the 6–8 Hz activity was indicative of the neuropsychiatric state change following medication intake. Those results were most evident in recordings from the ventral contacts closer to the limbic STN, while chronic stimulation settings covering the dorsal associative and motor STN captured a similar trend. STN low-frequency activity may serve as a biomarker for the acute neuropsychiatric state and neuropsychiatric responsiveness to dopamine and may inform future sensing-guided DBS strategies.
{"title":"Low-frequency activity in the subthalamic nucleus informs about the acute neuropsychiatric state in Parkinson’s disease","authors":"Elena Bernasconi, Alberto Averna, Valentina D’Onofrio, Deborah Amstutz, Damian M. Herz, Laura Alva, Andreia D. Magalhães, Katrin Petermann, Ines Debove, M. Lenard Lachenmayer, Andreas Nowacki, Claudio Pollo, Paul Krack, Mario Sousa, Gerd Tinkhauser","doi":"10.1038/s41531-025-01233-3","DOIUrl":"https://doi.org/10.1038/s41531-025-01233-3","url":null,"abstract":"Sensing-guided deep brain stimulation (DBS) offers potential to further optimize symptom control in Parkinson’s disease (PD) patients. Emerging evidence suggests that basal ganglia signals reflect not only motor, but also chronic neuropsychiatric symptoms. However, it remains unclear whether local field potentials (LFPs) can inform about acute neuropsychiatric states in PD, which we address in this work. Fourteen PD patients implanted with a brain-sense-enabled neurostimulator underwent an acute levodopa challenge OFF/ON stimulation one year after surgery. In each condition, resting state STN-LFPs were recorded, and the acute neuropsychiatric state was evaluated using the Neuropsychiatric Fluctuation Scale. The relationship between neuropsychiatric state and fluctuation scores with STN low-frequency activity (4–12 Hz) was assessed. An acute low neuropsychiatric state in the OFF-medication condition was associated with elevated theta/low-alpha power. Moreover, the 6–8 Hz activity was indicative of the neuropsychiatric state change following medication intake. Those results were most evident in recordings from the ventral contacts closer to the limbic STN, while chronic stimulation settings covering the dorsal associative and motor STN captured a similar trend. STN low-frequency activity may serve as a biomarker for the acute neuropsychiatric state and neuropsychiatric responsiveness to dopamine and may inform future sensing-guided DBS strategies.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"21 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968773","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 : 2026-01-15DOI: 10.1038/s41531-026-01261-7
Chae-Eun Moon, Seung Jae Lee, Haesol Shin, Hongkyung Kim, Jun-Ki Lee, Hyunjin Kim, Hyun Seung Kang, In Hee Moon, Sung Soo Kim, Hyung Keun Lee, Kyoung Yul Seo, Sung-Rae Cho, Yong Woo Ji
Parkinson’s disease (PD) affects motor and non-motor systems; however, retinal changes and their molecular basis are not well understood. Using a transgenic mouse model overexpressing A53T-mutant human α-synuclein, we examined retinal function, structure, and proteomics at 6- and 16 months. Early retinal dysfunction was detected by a reduction in scotopic oscillatory potential amplitudes on electroretinography. Optical coherence tomography showed early thinning of the retinal nerve fiber layer/ganglion cell layer, and photoreceptor layer, accompanied by thickening of the inner plexiform layer. Phosphorylated α-synuclein accumulation, increased glial fibrillary acidic protein, and loss of the ribbon synapse protein CtBP2 were observed. Proteomic profiling revealed stage-dependent alterations involving α-synuclein, oxidative stress markers, and crystallins. Network analysis showed progression from α-synuclein-associated disruption to inflammation and metabolic remodeling. These results highlight retinal alterations as early indicators of PD neurodegeneration and provide mechanistic insights into the molecular events that precede neuronal loss.
{"title":"Early retinal synaptic dysfunction and proteomic remodeling precede neurodegeneration in a Parkinson’s disease model","authors":"Chae-Eun Moon, Seung Jae Lee, Haesol Shin, Hongkyung Kim, Jun-Ki Lee, Hyunjin Kim, Hyun Seung Kang, In Hee Moon, Sung Soo Kim, Hyung Keun Lee, Kyoung Yul Seo, Sung-Rae Cho, Yong Woo Ji","doi":"10.1038/s41531-026-01261-7","DOIUrl":"https://doi.org/10.1038/s41531-026-01261-7","url":null,"abstract":"Parkinson’s disease (PD) affects motor and non-motor systems; however, retinal changes and their molecular basis are not well understood. Using a transgenic mouse model overexpressing A53T-mutant human α-synuclein, we examined retinal function, structure, and proteomics at 6- and 16 months. Early retinal dysfunction was detected by a reduction in scotopic oscillatory potential amplitudes on electroretinography. Optical coherence tomography showed early thinning of the retinal nerve fiber layer/ganglion cell layer, and photoreceptor layer, accompanied by thickening of the inner plexiform layer. Phosphorylated α-synuclein accumulation, increased glial fibrillary acidic protein, and loss of the ribbon synapse protein CtBP2 were observed. Proteomic profiling revealed stage-dependent alterations involving α-synuclein, oxidative stress markers, and crystallins. Network analysis showed progression from α-synuclein-associated disruption to inflammation and metabolic remodeling. These results highlight retinal alterations as early indicators of PD neurodegeneration and provide mechanistic insights into the molecular events that precede neuronal loss.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"16 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968737","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}
Oxidative phosphorylation (OXPHOS) and mitophagy are functionally interconnected cellular processes, the defects of which are considered key driving forces behind the pathogenesis of Parkinson’s disease (PD). UQCRC1, a core subunit of the mitochondrial respiratory chain complex III, is a recently identified familial PD gene whose pathogenic mutations result in OXPHOS stress. Given its importance, however, the role of UQCRC1 in idiopathic PD as well as mitophagy has not been investigated. In this study, we collected 19 datasets comprising postmortem substantia nigra from 150 cases of non-disease controls and 185 cases of PD or incidental Lewy body disease (iLBD), and the meta-analysis of the UQCRC1 mRNA level showed reduced expression in idiopathic PD, suggesting the potential of UQCRC1 as a biomarker. Leveraging the SH-SY5Y cells and fly models, we showed that mitophagy was impaired upon UQCRC1 mutation or depletion. Notably, insufficiency of PINK1 mRNA was associated with UQCRC1 deficiency, and overexpression of Pink1 rescued the locomotion and mitophagy defects in the fly models with neuronal loss of uqcrc1. Treatment with two PINK1 activators, kinetin and MTK458, resulted in similar protective effects in the fly and cell models. Overall, we identified OXPHOS stress led by deficiency of UQCRC1 as an etiology of mitophagy defects in PD and PINK1 as a therapeutic target for UQCRC1-associated PD.
{"title":"UQCRC1 deficiency impairs mitophagy via PINK1-dependent mechanisms in Parkinson’s disease","authors":"Jeng-Lin Li, Shu-Yi Huang, Po-Yu Huang, Ssu-Ju Fu, Yu-Jung Tsao, Wenying Chang, Cheng-Li Hong, Yu-Chien Hung, Pei-Han Liu, Liang-Chuan Lai, Chin-Hsien Lin, Wei-Chung Chiang, Chih-Chiang Chan","doi":"10.1038/s41531-026-01262-6","DOIUrl":"https://doi.org/10.1038/s41531-026-01262-6","url":null,"abstract":"Oxidative phosphorylation (OXPHOS) and mitophagy are functionally interconnected cellular processes, the defects of which are considered key driving forces behind the pathogenesis of Parkinson’s disease (PD). UQCRC1, a core subunit of the mitochondrial respiratory chain complex III, is a recently identified familial PD gene whose pathogenic mutations result in OXPHOS stress. Given its importance, however, the role of UQCRC1 in idiopathic PD as well as mitophagy has not been investigated. In this study, we collected 19 datasets comprising postmortem substantia nigra from 150 cases of non-disease controls and 185 cases of PD or incidental Lewy body disease (iLBD), and the meta-analysis of the UQCRC1 mRNA level showed reduced expression in idiopathic PD, suggesting the potential of UQCRC1 as a biomarker. Leveraging the SH-SY5Y cells and fly models, we showed that mitophagy was impaired upon UQCRC1 mutation or depletion. Notably, insufficiency of PINK1 mRNA was associated with UQCRC1 deficiency, and overexpression of Pink1 rescued the locomotion and mitophagy defects in the fly models with neuronal loss of uqcrc1. Treatment with two PINK1 activators, kinetin and MTK458, resulted in similar protective effects in the fly and cell models. Overall, we identified OXPHOS stress led by deficiency of UQCRC1 as an etiology of mitophagy defects in PD and PINK1 as a therapeutic target for UQCRC1-associated PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"48 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968740","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 : 2026-01-14DOI: 10.1038/s41531-026-01260-8
Chao Hou, Yang Wang, Lu Wang, Lizhi Yang, Shuo Li, Fang Nie, Wen He, Wei Zhang
Neurovascular coupling contributes to the regulation of cognitive function in Parkinson’s disease (PD). However, the correlation between structural and functional integrity of neurovascular unit in substantia nigra and cognitive impairment in PD remains poorly understood. Using super-resolution ultrasound imaging (SRUS), this study aimed to explore the interplay among dopaminergic neurons, microcirculation, and cognitive function in 6-hydroxydopamine-induced PD rat model. The model exhibited impaired motor and cognitive abilities, along with substantia nigra hyperechogenicity detected via transcranial sonography. SRUS revealed reduced microvascular density, complexity, and velocity, alongside increased vessel tortuosity in the substantia nigra. These changes were accompanied by elevated expression of MMP9, CD4, Iba 1, and GFAP, and decreased levels of TH, GLUT-1 and Laminin. Levodopa treatment prevented dopaminergic neurons degeneration, reduced substantia nigra hyperechogenicity, restored microvascular structure and function, as well as alleviated neuroinflammation, which may contribute to improved cognitive performance. These findings suggest that SRUS can effectively detect microvascular alterations in the substantia nigra in a 6-hydroxydopamine-induced PD rat model. Dysfunction neurovascular coupling, likely mediated by dopaminergic neuronal injury, may play a role in PD-related cognitive impairment.
{"title":"Super-resolution ultrasound imaging indirectly reveals neurovascular uncoupling in substantia nigra of a Parkinson’s disease model","authors":"Chao Hou, Yang Wang, Lu Wang, Lizhi Yang, Shuo Li, Fang Nie, Wen He, Wei Zhang","doi":"10.1038/s41531-026-01260-8","DOIUrl":"https://doi.org/10.1038/s41531-026-01260-8","url":null,"abstract":"Neurovascular coupling contributes to the regulation of cognitive function in Parkinson’s disease (PD). However, the correlation between structural and functional integrity of neurovascular unit in substantia nigra and cognitive impairment in PD remains poorly understood. Using super-resolution ultrasound imaging (SRUS), this study aimed to explore the interplay among dopaminergic neurons, microcirculation, and cognitive function in 6-hydroxydopamine-induced PD rat model. The model exhibited impaired motor and cognitive abilities, along with substantia nigra hyperechogenicity detected via transcranial sonography. SRUS revealed reduced microvascular density, complexity, and velocity, alongside increased vessel tortuosity in the substantia nigra. These changes were accompanied by elevated expression of MMP9, CD4, Iba 1, and GFAP, and decreased levels of TH, GLUT-1 and Laminin. Levodopa treatment prevented dopaminergic neurons degeneration, reduced substantia nigra hyperechogenicity, restored microvascular structure and function, as well as alleviated neuroinflammation, which may contribute to improved cognitive performance. These findings suggest that SRUS can effectively detect microvascular alterations in the substantia nigra in a 6-hydroxydopamine-induced PD rat model. Dysfunction neurovascular coupling, likely mediated by dopaminergic neuronal injury, may play a role in PD-related cognitive impairment.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"33 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968753","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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