Parkinson’s disease (PD) involves dopaminergic neuron loss and neuroinflammation, with leucine-rich repeat kinase 2 (LRRK2) mutations identified as major genetic risk factors. However, the pathogenic mechanism of the novel LRRK2-P1446L mutation remains unknown. Here, we designed LRRK2-P1446L mutant mice and demonstrated that the novel LRRK2-P1446L mutation drives neurodegeneration through death-associated protein kinase 1 (DAPK1) dysregulation. This mutation downregulates LRRK2 while upregulating DAPK1, which concurrently triggers microglial PI3K/Akt-dependent NF-κB activation (inducing IL-1β/IL-6/TNF-α expression) and neuronal mitochondrial apoptosis (via a Bax/Bcl-2 imbalance). Integrative multiomics revealed suppressed expression of the neuroprotective molecule tuftsin, which negatively correlated with DAPK1 expression and was linked to microbiota alterations. Our work establishes DAPK1 as a pivotal hub mediating neuroinflammation and apoptosis in LRRK2-related PD pathogenesis, and reveals novel associations with the gut-brain axis. These findings support DAPK1 inhibition as a promising therapeutic strategy, while the negative correlation with tuftsin suggests its restoration may be a potential future avenue for intervention.
{"title":"The LRRK2 P1446L mutation triggers dopaminergic neurodegeneration via DAPK1-mediated microglial neuroinflammation and neuronal apoptosis","authors":"Liuyan Ding, Hui Shu, Minshan Chen, Fengchu Liang, Tingting Gan, Xingting Huang, Xiaolei Liang, Kangting Luo, Linfeng Qiu, Weiqing Huang, Xiaoqin Zhu, Xiaoyun Huang, Wenlong Zhang, Pingyi Xu","doi":"10.1038/s41531-025-01234-2","DOIUrl":"https://doi.org/10.1038/s41531-025-01234-2","url":null,"abstract":"Parkinson’s disease (PD) involves dopaminergic neuron loss and neuroinflammation, with leucine-rich repeat kinase 2 (LRRK2) mutations identified as major genetic risk factors. However, the pathogenic mechanism of the novel LRRK2-P1446L mutation remains unknown. Here, we designed LRRK2-P1446L mutant mice and demonstrated that the novel LRRK2-P1446L mutation drives neurodegeneration through death-associated protein kinase 1 (DAPK1) dysregulation. This mutation downregulates LRRK2 while upregulating DAPK1, which concurrently triggers microglial PI3K/Akt-dependent NF-κB activation (inducing IL-1β/IL-6/TNF-α expression) and neuronal mitochondrial apoptosis (via a Bax/Bcl-2 imbalance). Integrative multiomics revealed suppressed expression of the neuroprotective molecule tuftsin, which negatively correlated with DAPK1 expression and was linked to microbiota alterations. Our work establishes DAPK1 as a pivotal hub mediating neuroinflammation and apoptosis in LRRK2-related PD pathogenesis, and reveals novel associations with the gut-brain axis. These findings support DAPK1 inhibition as a promising therapeutic strategy, while the negative correlation with tuftsin suggests its restoration may be a potential future avenue for intervention.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"248 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796447","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 progressive neurodegenerative disorder defined by motor impairments. However, people with PD (PwPD) experience a defined spectrum of non-motor symptoms, with gastrointestinal dysfunction the most common and earliest-presenting. Evidence suggests that PD pathology may originate in the gut, where microbial dysbiosis and immune dysregulation contribute to neuroinflammation, although mechanisms underlying this are unclear. PwPD (n = 31) and healthy controls (n = 28) were evaluated for clinical and gastrointestinal symptoms, faecal and plasma sample metabolomics, and comprehensive blood immunophenotyping. In PwPD, faecal samples exhibited reduced glutamate, succinate, and uracil concentrations, while plasma showed decreased 3-hydroxybutyrate and elevated creatine, succinate, and alanine levels. Immunophenotyping revealed a reduction in T cells, with evidence of altered effector capacity and functionality in CD4, CD8, MAIT and Vδ2 compartments. NK cells were expanded, while B cells were decreased in frequency with an enrichment of memory-like cells. Immune perturbations were correlated with levels of immunomodulatory metabolite succinate. Finally, clustering of blood parameters identified two PD endophenotypes distinguishable by gastrointestinal symptoms and T cell phenotypes associated with gut- and brain-tropism. These findings contribute to the growing understanding of metabolite-associated immune dysregulation in PD and highlight potential targets for early intervention in individuals presenting with gastrointestinal dysfunction.
{"title":"Immune and metabolic signatures characterise constipation-driven endophenotypes in Parkinson's disease.","authors":"Abbey Figliomeni,Samantha Winter,Madison Abonnel,Jade Kenna,Samantha Lodge,Luke Whiley,Andres Bernal,Jerome D Coudert,Jonathan Noonan,Belinda Kaskow,Ryan Anderton","doi":"10.1038/s41531-025-01212-8","DOIUrl":"https://doi.org/10.1038/s41531-025-01212-8","url":null,"abstract":"Parkinson's disease (PD) is a progressive neurodegenerative disorder defined by motor impairments. However, people with PD (PwPD) experience a defined spectrum of non-motor symptoms, with gastrointestinal dysfunction the most common and earliest-presenting. Evidence suggests that PD pathology may originate in the gut, where microbial dysbiosis and immune dysregulation contribute to neuroinflammation, although mechanisms underlying this are unclear. PwPD (n = 31) and healthy controls (n = 28) were evaluated for clinical and gastrointestinal symptoms, faecal and plasma sample metabolomics, and comprehensive blood immunophenotyping. In PwPD, faecal samples exhibited reduced glutamate, succinate, and uracil concentrations, while plasma showed decreased 3-hydroxybutyrate and elevated creatine, succinate, and alanine levels. Immunophenotyping revealed a reduction in T cells, with evidence of altered effector capacity and functionality in CD4, CD8, MAIT and Vδ2 compartments. NK cells were expanded, while B cells were decreased in frequency with an enrichment of memory-like cells. Immune perturbations were correlated with levels of immunomodulatory metabolite succinate. Finally, clustering of blood parameters identified two PD endophenotypes distinguishable by gastrointestinal symptoms and T cell phenotypes associated with gut- and brain-tropism. These findings contribute to the growing understanding of metabolite-associated immune dysregulation in PD and highlight potential targets for early intervention in individuals presenting with gastrointestinal dysfunction.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"20 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796252","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 : 2025-12-19DOI: 10.1038/s41531-025-01238-y
Roy Dayan,Serafima Dubnov,Hagit Turm,Michelle Grunin,Shahar Shohat,Salim T Khoury,Ami Citri,Tamar Harel,David Arkadir
Blood transcriptomic signatures for Parkinson's disease (PD) diagnosis have failed to integrate into clinical practice despite decades of translational efforts. We evaluated the classification performance of 13 published coding RNA-based signatures using both a large public dataset and data we collected prospectively in a controlled clinical study of levodopa-naïve patients and healthy controls. Our results show that gene overlap between signatures is low but significant (2.7%, p < 0.001) and enriched for lipid metabolism genes. Most signatures (10/13) remained significant when tested on the Parkinson's Progression Markers Initiative (PPMI) dataset, though with lower classification performance than previously reported (median AUC: 59.7%). Performance improved for GBA1-associated PD. Rigorous standardization of clinical and environmental parameters in our prospective study (30 participants) failed to improve transcriptome-based classification. We conclude that while the search for a universal blood-based PD transcriptome may elucidate disease pathophysiology, its clinical utility is inherently limited.
{"title":"Inherent variability limits clinical utility of reproducible Parkinson's transcriptomics signatures.","authors":"Roy Dayan,Serafima Dubnov,Hagit Turm,Michelle Grunin,Shahar Shohat,Salim T Khoury,Ami Citri,Tamar Harel,David Arkadir","doi":"10.1038/s41531-025-01238-y","DOIUrl":"https://doi.org/10.1038/s41531-025-01238-y","url":null,"abstract":"Blood transcriptomic signatures for Parkinson's disease (PD) diagnosis have failed to integrate into clinical practice despite decades of translational efforts. We evaluated the classification performance of 13 published coding RNA-based signatures using both a large public dataset and data we collected prospectively in a controlled clinical study of levodopa-naïve patients and healthy controls. Our results show that gene overlap between signatures is low but significant (2.7%, p < 0.001) and enriched for lipid metabolism genes. Most signatures (10/13) remained significant when tested on the Parkinson's Progression Markers Initiative (PPMI) dataset, though with lower classification performance than previously reported (median AUC: 59.7%). Performance improved for GBA1-associated PD. Rigorous standardization of clinical and environmental parameters in our prospective study (30 participants) failed to improve transcriptome-based classification. We conclude that while the search for a universal blood-based PD transcriptome may elucidate disease pathophysiology, its clinical utility is inherently limited.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"40 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777400","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 : 2025-12-17DOI: 10.1038/s41531-025-01186-7
Guangying Pei, Xiao Yang, Han Liu, Mengxuan Hu, Keke Chen, Cuiping Xue, Zhaohui Jin, Li Wang, Chunyu Zhang, Boyan Fang, Tianyi Yan
Individuals with mild cognitive impairment (MCI) in Parkinson’s disease (PD) are significantly susceptible to developing dementia. Investigating cortical dynamics within the posterior parietal cortex (PPC) may elucidate the mechanisms underlying cognitive decline in PD. Using combined transcranial magnetic stimulation-electroencephalography, this study assessed cortical excitability, time-frequency oscillations, and functional network dynamics after stimulation of the right PPC in 45 PD patients (23 with MCI, 22 with normal cognition). Results showed that PD-MCI patients exhibited increased TMS-evoked potentials across the frontal-parietal-occipital cortex compared to cognitively normal PD patients, accompanied by enhanced theta and alpha oscillation synchronization. Functional connectivity analysis revealed higher global efficiency and lower average shortest path length within theta-band frontoparietal networks in PD-MCI, which correlated with poorer cognitive performance. These results highlight hyperactive cortical responses and hyperconnected low-frequency brain networks in PD-MCI following right PPC stimulation, implicating the PPC as a potential intervention target to mitigate cognitive decline in PD.
{"title":"Cortical dynamics and network alterations in Parkinson’s disease with mild cognitive impairment: TMS-EEG study of the posterior parietal cortex","authors":"Guangying Pei, Xiao Yang, Han Liu, Mengxuan Hu, Keke Chen, Cuiping Xue, Zhaohui Jin, Li Wang, Chunyu Zhang, Boyan Fang, Tianyi Yan","doi":"10.1038/s41531-025-01186-7","DOIUrl":"https://doi.org/10.1038/s41531-025-01186-7","url":null,"abstract":"Individuals with mild cognitive impairment (MCI) in Parkinson’s disease (PD) are significantly susceptible to developing dementia. Investigating cortical dynamics within the posterior parietal cortex (PPC) may elucidate the mechanisms underlying cognitive decline in PD. Using combined transcranial magnetic stimulation-electroencephalography, this study assessed cortical excitability, time-frequency oscillations, and functional network dynamics after stimulation of the right PPC in 45 PD patients (23 with MCI, 22 with normal cognition). Results showed that PD-MCI patients exhibited increased TMS-evoked potentials across the frontal-parietal-occipital cortex compared to cognitively normal PD patients, accompanied by enhanced theta and alpha oscillation synchronization. Functional connectivity analysis revealed higher global efficiency and lower average shortest path length within theta-band frontoparietal networks in PD-MCI, which correlated with poorer cognitive performance. These results highlight hyperactive cortical responses and hyperconnected low-frequency brain networks in PD-MCI following right PPC stimulation, implicating the PPC as a potential intervention target to mitigate cognitive decline in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"22 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765576","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 : 2025-12-14DOI: 10.1038/s41531-025-01202-w
Yi Fang, Rebecca Hardy, Kristine Yaffe, Simon J. Little, Caroline M. Tanner, Yue Leng
Sleep disturbances are both prodromes and potential risk factors for Parkinson’s disease (PD), yet associations between long-term sleep patterns and PD remain unclear. We analyzed data from two online cohorts—PPMI-Online (n = 15,905) and Fox Insight (n = 1929)—to examine associations between self-reported sleep duration trajectories across life stages and PD risk and age at onset (AAO). Latent class growth analysis identified distinct trajectories, linear and logistic regression examined their associations with PD risk and AAO, adjusting for demographics, lifestyle, and comorbidities. In PPMI-Online, sleep duration was generally stable in early adulthood with divergence in midlife. Compared to stable sleepers (7–8 h/day), individuals with midlife reductions (6–7 to ≤5–6 h/day: OR = 1.90; 7–8 to ≤6–7 h/day: OR = 1.64) and persistent short sleep (≤6 h/day: OR = 1.41) had higher PD risk, independent of comorbidities. Similar patterns were observed in probable prodromal PD. Persistent short sleep and sleep decline were also linked to earlier AAO (up to –4.23 years) across cohorts. These findings suggest that midlife sleep reduction may signal early PD, while chronic short sleep may represent a modifiable risk factor, highlighting the need for prospective studies to explore early detection and prevention potential.
{"title":"Self-perceived life course sleep duration trajectories and risk and age at onset of Parkinson’s disease","authors":"Yi Fang, Rebecca Hardy, Kristine Yaffe, Simon J. Little, Caroline M. Tanner, Yue Leng","doi":"10.1038/s41531-025-01202-w","DOIUrl":"https://doi.org/10.1038/s41531-025-01202-w","url":null,"abstract":"Sleep disturbances are both prodromes and potential risk factors for Parkinson’s disease (PD), yet associations between long-term sleep patterns and PD remain unclear. We analyzed data from two online cohorts—PPMI-Online (n = 15,905) and Fox Insight (n = 1929)—to examine associations between self-reported sleep duration trajectories across life stages and PD risk and age at onset (AAO). Latent class growth analysis identified distinct trajectories, linear and logistic regression examined their associations with PD risk and AAO, adjusting for demographics, lifestyle, and comorbidities. In PPMI-Online, sleep duration was generally stable in early adulthood with divergence in midlife. Compared to stable sleepers (7–8 h/day), individuals with midlife reductions (6–7 to ≤5–6 h/day: OR = 1.90; 7–8 to ≤6–7 h/day: OR = 1.64) and persistent short sleep (≤6 h/day: OR = 1.41) had higher PD risk, independent of comorbidities. Similar patterns were observed in probable prodromal PD. Persistent short sleep and sleep decline were also linked to earlier AAO (up to –4.23 years) across cohorts. These findings suggest that midlife sleep reduction may signal early PD, while chronic short sleep may represent a modifiable risk factor, highlighting the need for prospective studies to explore early detection and prevention potential.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"232 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746783","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 : 2025-12-13DOI: 10.1038/s41531-025-01203-9
Kexin Wang, Nirbhay Narayan Yadav, Zijiang Yang, Ted M. Dawson, Peter van Zijl, Kelly A. Mills, Jiadi Xu, Jannik Prasuhn
Parkinson’s disease (PD) is a progressive neurodegenerative disorder featured impaired bioenergetics and mitochondrial dysfunction. Creatine (Cr) supplementation has been suggested as a pathophysiology-targeted treatment strategy; however, clinical outcomes remain inconsistent despite encouraging preclinical findings. The lack of methods to measure Cr distribution in the human brain may hinder the investigation. This study utilized a novel neuroimaging technique, guanidino chemical exchange saturation transfer (GuanCEST) MRI, to assess regional Cr levels in patients with PD (PwPD) and healthy controls (HCs). Twenty-five patients with PD and 24 age- and sex-matched HCs were enrolled. GuanCEST values in the caudate nucleus were significantly lower in PwPD (1.67 ± 0.26%) than HCs (1.82 ± 0.16%), p = 0.023. Moreover, GuanCEST signal reductions correlated with increasing PD severity, particularly in thalamic subregions. Kendall’s correlation revealed a significant negative correlation between GuanCEST values in the internal medullary lamina and MDS-UPDRS-III scores (r = −0.44, p = 0.03). Regional ANCOVA further indicated that GuanCEST values in this region decreased by approximately 0.01% per unit increase in MDS-UPDRS-III (p = 0.007), adjusted for age and sex. These findings highlight GuanCEST MRI’s potential as a noninvasive biomarker of Cr metabolism in PD, offering insights into disease mechanisms, therapeutic optimization, and clinical trial designs.
{"title":"Creatine-weighted imaging in patients with Parkinson’s disease","authors":"Kexin Wang, Nirbhay Narayan Yadav, Zijiang Yang, Ted M. Dawson, Peter van Zijl, Kelly A. Mills, Jiadi Xu, Jannik Prasuhn","doi":"10.1038/s41531-025-01203-9","DOIUrl":"https://doi.org/10.1038/s41531-025-01203-9","url":null,"abstract":"Parkinson’s disease (PD) is a progressive neurodegenerative disorder featured impaired bioenergetics and mitochondrial dysfunction. Creatine (Cr) supplementation has been suggested as a pathophysiology-targeted treatment strategy; however, clinical outcomes remain inconsistent despite encouraging preclinical findings. The lack of methods to measure Cr distribution in the human brain may hinder the investigation. This study utilized a novel neuroimaging technique, guanidino chemical exchange saturation transfer (GuanCEST) MRI, to assess regional Cr levels in patients with PD (PwPD) and healthy controls (HCs). Twenty-five patients with PD and 24 age- and sex-matched HCs were enrolled. GuanCEST values in the caudate nucleus were significantly lower in PwPD (1.67 ± 0.26%) than HCs (1.82 ± 0.16%), p = 0.023. Moreover, GuanCEST signal reductions correlated with increasing PD severity, particularly in thalamic subregions. Kendall’s correlation revealed a significant negative correlation between GuanCEST values in the internal medullary lamina and MDS-UPDRS-III scores (r = −0.44, p = 0.03). Regional ANCOVA further indicated that GuanCEST values in this region decreased by approximately 0.01% per unit increase in MDS-UPDRS-III (p = 0.007), adjusted for age and sex. These findings highlight GuanCEST MRI’s potential as a noninvasive biomarker of Cr metabolism in PD, offering insights into disease mechanisms, therapeutic optimization, and clinical trial designs.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"47 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746786","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}
Variants in GBA1 represent the most prevalent genetic risk factors for Parkinson's disease (PD), yet how environmental exposures interact with these mutations to drive disease remains unclear. Epidemiological evidence implicates high dairy consumption as a potential modifiable risk factor for PD, but the mechanistic basis remains elusive. Here, we identify hepatic deposition of phosphorylated α-synuclein (pα-syn) in two PD patients carrying the pathogenic GBA1 L444P variant with histories of excessive dairy intake. Using Gba1L444P/+ mice, we demonstrate that a dairy-rich diet enriched in calcium and casein could induce pathological α-syn aggregation within Kupffer cells (KCs) of the liver. Proteomic profiling reveals that this diet triggers mitochondrial oxidative stress and aggravates GBA1 mutation-induced autophagy defects in KCs, creating a permissive environment for α-synucleinopathy. Notably, hepatic pα-syn pathology propagates to discrete brain regions, including the dorsal nucleus of the vagus nerve, substantia nigra, striatum, and prefrontal cortex, leading to both motor and cognitive impairments. Surgical disruption of liver-brain communication via liver transplantation or hepatic denervation can postpone cerebral pα-syn deposition, confirming a neural conduit for disease transmission. These findings establish the liver as a novel origin site for α-syn pathology in a genetically susceptible context, and define a previously unrecognized liver-brain axis in PD pathogenesis. Our work highlights the interplay between environmental and genetic factors in shaping α-syn dynamics and uncovers potential targets for early intervention in PD.
{"title":"Dairy-rich diet triggers hepatic α-synuclein pathology via the liver-brain axis in GBA1-related Parkinson's disease.","authors":"Yongkang Chen,Mingming Ma,Rui Zhang,Canan Guo,Xuebing Ding,Jiuqi Wang,Chi Qin,Renyi Feng,Haojie Meng,Heng Wu,Weitao Que,Xuejing Wang,Beisha Tang","doi":"10.1038/s41531-025-01211-9","DOIUrl":"https://doi.org/10.1038/s41531-025-01211-9","url":null,"abstract":"Variants in GBA1 represent the most prevalent genetic risk factors for Parkinson's disease (PD), yet how environmental exposures interact with these mutations to drive disease remains unclear. Epidemiological evidence implicates high dairy consumption as a potential modifiable risk factor for PD, but the mechanistic basis remains elusive. Here, we identify hepatic deposition of phosphorylated α-synuclein (pα-syn) in two PD patients carrying the pathogenic GBA1 L444P variant with histories of excessive dairy intake. Using Gba1L444P/+ mice, we demonstrate that a dairy-rich diet enriched in calcium and casein could induce pathological α-syn aggregation within Kupffer cells (KCs) of the liver. Proteomic profiling reveals that this diet triggers mitochondrial oxidative stress and aggravates GBA1 mutation-induced autophagy defects in KCs, creating a permissive environment for α-synucleinopathy. Notably, hepatic pα-syn pathology propagates to discrete brain regions, including the dorsal nucleus of the vagus nerve, substantia nigra, striatum, and prefrontal cortex, leading to both motor and cognitive impairments. Surgical disruption of liver-brain communication via liver transplantation or hepatic denervation can postpone cerebral pα-syn deposition, confirming a neural conduit for disease transmission. These findings establish the liver as a novel origin site for α-syn pathology in a genetically susceptible context, and define a previously unrecognized liver-brain axis in PD pathogenesis. Our work highlights the interplay between environmental and genetic factors in shaping α-syn dynamics and uncovers potential targets for early intervention in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"3 11 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746702","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 : 2025-12-13DOI: 10.1038/s41531-025-01201-x
Raquel Rodriguez-Aller,Beatriz Romero-Quineche,Marc Morissette,Razan Sheta,Thérèse Di Paolo,Armen Saghatelyan,Abid Oueslati
Presynaptic accumulation of misfolded α-synuclein (α-syn) and altered synaptic transmission are considered early events in the pathogenesis of Parkinson's disease (PD), suggesting a potential causal link between these two events. However, the mechanisms by which α-syn aggregation induces synaptic dysfunction and the subsequent progressive neurodegeneration remain elusive. In the present study we leveraged the high temporal resolution of the Light-Inducible Protein Aggregation (LIPA) system in vivo and in human dopaminergic neurons to explore the early sequence of α-syn-induced pathological events leading to synaptopathy. We observed that nigrostriatal axonal transport and presynaptic accumulation of α-syn aggregates altered the activity of different neuronal populations in the mouse striatum. The results of histological and metabolite analyses show that presynaptic accumulation of α-syn induced a shift in the activation pattern of D1- and D2-expressing striatal medium spiny neurons, caused an increase in the size and density of dopaminergic synapses, and disrupted striatal dopamine signaling. Altogether, our findings reveal that the accumulation of α-syn in dopaminergic terminals triggered early presynaptic impairments, which subsequently altered striatal neuronal activity. Our study provides new insights into the molecular mechanisms underlying early synaptopathy in PD.
{"title":"Optogenetic-induced α-synuclein accumulation reveals early synaptic dysfunction in experimental models of Parkinson's disease.","authors":"Raquel Rodriguez-Aller,Beatriz Romero-Quineche,Marc Morissette,Razan Sheta,Thérèse Di Paolo,Armen Saghatelyan,Abid Oueslati","doi":"10.1038/s41531-025-01201-x","DOIUrl":"https://doi.org/10.1038/s41531-025-01201-x","url":null,"abstract":"Presynaptic accumulation of misfolded α-synuclein (α-syn) and altered synaptic transmission are considered early events in the pathogenesis of Parkinson's disease (PD), suggesting a potential causal link between these two events. However, the mechanisms by which α-syn aggregation induces synaptic dysfunction and the subsequent progressive neurodegeneration remain elusive. In the present study we leveraged the high temporal resolution of the Light-Inducible Protein Aggregation (LIPA) system in vivo and in human dopaminergic neurons to explore the early sequence of α-syn-induced pathological events leading to synaptopathy. We observed that nigrostriatal axonal transport and presynaptic accumulation of α-syn aggregates altered the activity of different neuronal populations in the mouse striatum. The results of histological and metabolite analyses show that presynaptic accumulation of α-syn induced a shift in the activation pattern of D1- and D2-expressing striatal medium spiny neurons, caused an increase in the size and density of dopaminergic synapses, and disrupted striatal dopamine signaling. Altogether, our findings reveal that the accumulation of α-syn in dopaminergic terminals triggered early presynaptic impairments, which subsequently altered striatal neuronal activity. Our study provides new insights into the molecular mechanisms underlying early synaptopathy in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"20 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746703","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 : 2025-12-13DOI: 10.1038/s41531-025-01206-6
Susan H Fox,Daniel G Luca,Ronald B Postuma,Roongroj Bhidayasiri,Francisco Cardoso,Gabor G Kovacs,Regina Katzenschlager,Claudia Trenkwalder
The 2015 International Parkinson and Movement Disorder Society (MDS) Diagnostic criteria for Parkinson Disease are based on expert consensus opinion and defines core motor features, 'Absolute Exclusion Criteria' and a balance of 'Supportive Criteria' and 'Red Flags'. To assess validity of each criterion in pathologically-confirmed cases, a scoping literature review between 1988-2024 using search terms for clinicopathological PD and atypical parkinsonian disorders identified 28 articles. Supportive criteria were higher in PD, with excellent levodopa response and rest tremor most useful. Absolute exclusion criteria and red flags were present more often in atypical parkinsonian disorders. However, supranuclear gaze palsy, rapid progression of gait impairment to wheelchair requirement and bilateral symptoms were reported in >5% PD. Data was limited by few appropriate pathological studies with sufficient clinical data; challenges in applying highly-specific definitions to retrospective studies and likely co-pathologies. This review provides empiric data to support some items of the MDS Criteria with future potential refinement.
{"title":"Revisiting the 2015 MDS diagnostic criteria for Parkinson disease: insights from autopsy-confirmed cases.","authors":"Susan H Fox,Daniel G Luca,Ronald B Postuma,Roongroj Bhidayasiri,Francisco Cardoso,Gabor G Kovacs,Regina Katzenschlager,Claudia Trenkwalder","doi":"10.1038/s41531-025-01206-6","DOIUrl":"https://doi.org/10.1038/s41531-025-01206-6","url":null,"abstract":"The 2015 International Parkinson and Movement Disorder Society (MDS) Diagnostic criteria for Parkinson Disease are based on expert consensus opinion and defines core motor features, 'Absolute Exclusion Criteria' and a balance of 'Supportive Criteria' and 'Red Flags'. To assess validity of each criterion in pathologically-confirmed cases, a scoping literature review between 1988-2024 using search terms for clinicopathological PD and atypical parkinsonian disorders identified 28 articles. Supportive criteria were higher in PD, with excellent levodopa response and rest tremor most useful. Absolute exclusion criteria and red flags were present more often in atypical parkinsonian disorders. However, supranuclear gaze palsy, rapid progression of gait impairment to wheelchair requirement and bilateral symptoms were reported in >5% PD. Data was limited by few appropriate pathological studies with sufficient clinical data; challenges in applying highly-specific definitions to retrospective studies and likely co-pathologies. This review provides empiric data to support some items of the MDS Criteria with future potential refinement.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"1 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746704","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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