NPJ Parkinson's Disease最新文献

{"title":"Sleep deprivation exacerbates Parkinson’s disease via PPARγ–PLIN4-mediated microglial lipid droplet accumulation and neuroinflammation","authors":"Tongtong Deng, Xiaomei Liang, Zhongling Fu, Mengshi Liao, Baoyu Zhu, Jiezhu Feng, Kaicheng Wang, Kun Nie, Lijuan Wang, Piao Zhang, Yuhu Zhang","doi":"10.1038/s41531-026-01543-0","DOIUrl":"https://doi.org/10.1038/s41531-026-01543-0","url":null,"abstract":"Sleep disturbances are common early non-motor features of Parkinson’s disease (PD), yet how chronic sleep loss accelerates PD progression remains poorly understood. Here, we demonstrate in an MPTP-induced mouse model that sleep deprivation (SD) triggers robust neuroinflammation and metabolic reprogramming in the Substantia Nigra Pars Compacta (SNpc), accompanied by marked accumulation of lipid droplets (LDs) within microglia. Transcriptomic and histological analyses identified Perilipin 4 (PLIN4) as a sleep deprivation-responsive LD-associated gene in microglia. PLIN4 overexpression promoted LD accumulation, mitochondrial stress, and inflammatory activation, whereas PLIN4 knockdown attenuated these phenotypes and reduced SD/MPTP-induced microglial LD burden and behavioral impairment in vivo. Mechanistically, SD/PD conditions were associated with reduced PPARγ expression and increased PLIN4 accumulation. CUT&Tag (Cleavage Under Targets and Tagmentation) analysis revealed PPARγ occupancy at a Plin4-associated regulatory region, and motif-mutated reporter assays confirmed PPARγ responsiveness of this region, supporting a context-dependent regulatory relationship between PPARγ and PLIN4. Pharmacological activation and microglia-targeted overexpression of PPARγ reduced PLIN4 expression, microglial LD accumulation, neuroinflammatory activation, and motor deficits. Together, our findings identify a sleep-sensitive PPARγ-PLIN4 lipid-inflammatory pathway in microglia and suggest that microglial LD remodeling contributes to vulnerability to dopaminergic neurodegeneration.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"38 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148853520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electroencephalographic slowing during REM sleep as a marker of cholinergic network dysfunction in Lewy body disorders","authors":"Jack Anderson, Lachlan Churchill, Ajay Konuri, Anna Ignatavicius, Garry Cho, Aaron Lam, Angela L. D’Rozario, Sharon L. Naismith, Ronald R. Grunstein, Simon JG Lewis, Elie Matar","doi":"10.1038/s41531-026-01515-4","DOIUrl":"https://doi.org/10.1038/s41531-026-01515-4","url":null,"abstract":"Lewy body disorders (LBD), including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), are the second most common cause of neurodegeneration in older adults. Dysfunction of cholinergic brainstem and forebrain pathways, including the pedunculopontine nucleus (PPN) and nucleus basalis of Meynert (NBM), has been implicated in cognitive decline in LBD, yet accessible functional markers remain limited. Because REM sleep depends on ascending cholinergic pathways, alterations in REM electroencephalographic (EEG) activity may provide a window onto their integrity. Twenty-four participants with DLB, 36 with PD, and 44 controls underwent neuropsychological testing and polysomnography, with a subset completing structural and resting-state MRI. EEG spectral power across δ, θ, α, σ and β bands was quantified during REM sleep and the REM EEG slowing ratio (δ + θ)/(α + σ + β) derived for frontal, central and occipital regions. NBM volumes were derived from T1-weighted images, and functional connectivity examined between the NBM and large-scale networks, and the PPN and thalamus. DLB participants had greater occipital REM EEG slowing than PD and controls, a regionally specific rather than global effect. Across LBD, REM slowing was most robustly associated with PPN–thalamic connectivity, with weaker NBM connectivity and no NBM volume association. Greater occipital REM EEG slowing correlated with worse global cognition and executive function. These findings demonstrate that occipital REM EEG slowing reflects PPN–thalamic and, to a lesser extent, NBM network dysfunction, is associated with clinically relevant cognitive impairment in LBD, and may represent a non-invasive, transdiagnostic marker for disease monitoring, prognosis, and stratification in clinical trials.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"133 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148853519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Classification of fallers in Parkinson's disease through machine learning based feature analysis.","authors":"Minkyung Kim, Sumin Kim, Do-Young Kwon, MyungJin Chung, Jin Whan Cho, Hakje Yoo, Jinyoung Youn","doi":"10.1038/s41531-026-01468-8","DOIUrl":"10.1038/s41531-026-01468-8","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"12 1","pages":""},"PeriodicalIF":8.5,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13503737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The psychotic complications of subcutaneous foslevodopa/foscarbidopa infusions – retrospective observational real-world data study including 198 patients","authors":"Joanna S. Siuda, Jakub Malkiewicz, Mateusz Toś, Agata Dymek, Monika Figura, Łukasz Milanowski, Stanisław Szlufik, Dariusz Koziorowski, Agata Gajos, Ewa Pruska, Andrzej S. Bogucki, Paulina Konieczna, Andrzej W. Bereza, Sławomir Budrewicz, Aleksandra Bręk, Agnieszka Gajda, Radosław Piekarski, Jarosław Sławek","doi":"10.1038/s41531-026-01546-x","DOIUrl":"https://doi.org/10.1038/s41531-026-01546-x","url":null,"abstract":"Continuous foslevodopa/foscarbidopa subcutaneous infusion (LDp/CDp) is a new therapeutic option for advanced Parkinson’s disease (PD). The treatment is effective, but might be associated with psychotic symptoms (PS). The aim of the study was to assess the prevalence and factors associated with PS during LDp/CDp therapy, defined as delusions and formed hallucinations with or without preserved insight. A retrospective chart review was performed in 6 tertiary movement disorders centers in Poland, and 198 patients were included. Demographic data, PD course, MDS-UPDRS p.III OFF, and treatment before and after LDp/CDp initiation were recorded. Fifty-seven (28.8%) patients developed PS, leading to LDp/CDp treatment discontinuation in 16 (8.1%) patients. A univariate analysis was performed, and factors with p < 0.15 were included in the logistic regression model. Regression analysis revealed that the only statistically significant factor associated with PS after LDp/CDp initiation was the presence of PS at any time during the PD course (OR 6.89; 95%CI 2.76–17.15; p < 0.001). Psychotic symptoms associated with LDp/CDp treatment in the real-world setting are more common than in randomized controlled trials, and related to the presence of PS at any time before LDp/CDp initiation. Patients with a previous history of PS should be selected with caution and monitored after treatment initiation.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"7 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alanine tRNA fragments interacting with MEG3 long splice variant show tissue-, cellular compartment- and disease severity-dependent changes in Parkinson’s disease","authors":"Tamara Zorbaz, Estelle R. Bennett, Shani Vaknine Treidel, Nimrod Madrer, Arbel Zeira, David S. Greenberg, Iddo Paldor, Hermona Soreq","doi":"10.1038/s41531-026-01541-2","DOIUrl":"https://doi.org/10.1038/s41531-026-01541-2","url":null,"abstract":"Long non-coding RNAs (lncRNAs) and tRNA fragments (tRFs) have emerged as important regulators in Parkinson’s disease (PD), but much remains unknown regarding their interactions. We report here that the long splice variant of MEG3 lncRNA interacts with alanine tRNA 3’-end fragments (3’-tRFs-Ala), and that both showed dysregulated levels in the substantia nigra of PD patients. Additionally, carriers of PD-risk mutations (LRRK2+, GBA+, SNCA+) had decreased levels of 3’-tRFs-Ala in their blood, and in GBA+ PD patients, reduced levels correlated with the severity of autonomic and sensory non-motor impairments. Paraquat-induced oxidative stress in neuroblastoma cells decreased 3’-tRFs-Ala levels in the nucleus but increased them in the cytoplasm, highlighting acute changes in subcellular localization. Simultaneously, 3’-tRFs-Ala bind nuclear spliceosome and cytoplasmic aminoacyl-tRNA synthetase proteins, suggesting an additional level of post-transcriptional regulation in neuronal and peripheral immune cells. Overall, the interacting MEG3 long splice variant and 3’-tRFs-Ala emerged as non-coding RNAs with dynamic and spatiotemporal roles in PD pathology.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"11 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative proteomic analysis of environmental and genetic models of Parkinson’s disease highlights the role of purine metabolism","authors":"Pablo Reina-Gonzalez, Müberra Fatma Cesur, Aiesha Anchan, Abdulla Abu-Salah, Tunahan Çakır, Emir Malovic, Souvarish Sarkar","doi":"10.1038/s41531-026-01542-1","DOIUrl":"https://doi.org/10.1038/s41531-026-01542-1","url":null,"abstract":"Parkinson’s Disease (PD) is the second most common neurodegenerative disease, with many cases attributed to environmental exposures. Paraquat (PQ), is a pesticide and neurotoxicant strongly associated with increased PD risk. PQ is a weak inhibitor of complex I of the electron transport chain, and while its acute toxicity is well understood, the mechanism by which PQ exposure contributes to PD pathophysiology remains unclear. Additionally, the mechanism of PQ neurotoxicity has not been effectively related to genetic forms of PD. Given that PD is a heterogeneous disease with genetic and environmental determinants, we systematically compared proteomic changes that occur in genetic and environmental models of PD. Herein, we leveraged untargeted omics approaches to differentiate between peripheral and CNS-specific changes in the proteome. We performed a comparative proteomic analysis on the heads and bodies of Drosophila models of PQ ingestion and neuronal α-synuclein expression. Additionally, we validated the findings with metabolomic analysis of brainstems from a murine PQ inhalation model. Our findings indicate shared dysregulated pathways across all models, highlighting similar mechanisms. Specifically, we identified a glia-specific role in purine nucleotide metabolism upstream of inosine catabolism, which may protect against PQ neurotoxicity. This work identifies potential biomarkers and targets for drug intervention.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"57 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted degradation of alpha-synuclein impedes PFF-induced aggregation","authors":"Bill Carton, Géraldine Gelders, Gajanan Sathe, Jin-Feng Zhao, Nur M. Kocaturk, Sascha Roth, Thomas J. Macartney, Joke Van Elsen, Louis De Muynck, Arjan Buist, Diederik Moechars, Gopal P. Sapkota","doi":"10.1038/s41531-026-01539-w","DOIUrl":"https://doi.org/10.1038/s41531-026-01539-w","url":null,"abstract":"Accumulation of misfolded α-synuclein protein in intracellular inclusion bodies of dopaminergic neurons underlies the pathogenesis of Synucleinopathies, which include Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). Therefore, preventing the accumulation of misfolded α-synuclein in dopaminergic neurons or their clearance could in principle offer intervention strategies against Synucleinopathies, which currently remain untreatable. In this study, we employ the Affinity-directed PROtein Missile (AdPROM) system consisting of the substrate receptor of the CUL2-E3 ligase complex VHL and a nanobody selectively recognising the human α-synuclein protein and demonstrate targeted degradation of endogenous α-synuclein from human cell lines with remarkable selectivity. We further demonstrate that targeted degradation of α-synuclein impedes the pre-formed fibril (PFF)-induced aggregation of α-synuclein in primary neurons derived from rats expressing human α-synuclein. This approach also represents the first demonstration of nanobody-guided proteasomal degradation of some reported clinically relevant α-synuclein variants.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"1 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regional reduction of high-energy phosphorus metabolites characterizes the cerebellar subtype of multiple system atrophy","authors":"Jannik Prasuhn, Christina Bodemann, Britt Ebeling, Katharina Reuther, Sinja S. Großer, Jan Uter, Julia Henkel, Henrike Hanssen, Norbert Brüggemann","doi":"10.1038/s41531-026-01537-y","DOIUrl":"https://doi.org/10.1038/s41531-026-01537-y","url":null,"abstract":"Multiple system atrophy (MSA) is a severe neurodegenerative disorder with various underlying pathophysiological features. Mitochondrial dysfunction has been implied as a viable treatment target in patients with MSA. Yet, there is a lack of in-vivo studies examining regional metabolic differences between the Parkinsonian (MSAp) and the cerebellar (MSAc) subtype of MSA. Twenty-four patients with MSA (12 patients with MSAp and 12 patients with MSAc), 24 patients with Parkinson’s disease (PD), and 24 age- and sex-matched healthy controls (HCs) underwent clinical evaluations and multimodal neuroimaging, including 31P-MRSI targeting the basal ganglia and the cerebellum. Ratios of high-energy phosphorus-containing metabolites (HEPs) were compared between groups. Only patients with MSAc showed decreased HEP levels in the cerebellum. Conversely, no differences in basal ganglia HEP levels appeared between both MSA subtypes, patients with PD, or HCs. Our findings provide preliminary in-vivo evidence for regionally detectable bioenergetic alterations in the cerebellum of patients with MSAc, while basal ganglia results, particularly in MSAp, require cautious interpretation because of the spatial-resolution limits of the present 31P-MRSI approach.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"77 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baseline clinical features outperform structural MRI in predicting rapid cognitive and motor decline in Parkinson’s disease","authors":"Yusen Wu, Jose A. Santiago, Tatjana Rundek, Phuong Nguyen, Yelena Yesha, Matthew Feldman, Marina Lucia Sarno, Priyanka Atit, Jacob Miller, Tara Najafi, Ayham Alkhachroum, Ihtsham U. Haq","doi":"10.1038/s41531-026-01530-5","DOIUrl":"https://doi.org/10.1038/s41531-026-01530-5","url":null,"abstract":"Cognitive and motor impairments are common in Parkinson’s disease (PD), but rapid decline trajectories remain difficult to predict at the individual level. Identifying reliable early-stage prognostic markers could define disease-modification windows and improve trial enrichment. Classification models were developed to predict rapid decline, defined as a decrease of ≥5 points on the Montreal Cognitive Assessment (MoCA) and an increase of ≥10 points on the MDS-UPDRS3 from baseline to any timepoint 3–5 years post-baseline. Models were trained using longitudinal MRI-derived regional atrophy rates and baseline clinical features. Model performance was evaluated using AUROC and complementary classification metrics; calibration, performance ceilings, and clinical utility were further assessed using calibration curves and decision curve analysis (DCA). Feature analysis was performed to identify clinically informative predictors. Structural MRI (e.g., annualized atrophy rate) demonstrated limited prognostic utility for individual-level prediction; this remained true with finer-grained atlases. In contrast, baseline clinical features yielded substantially stronger discrimination for both outcomes. Notably, cognitive prediction remained robust after removal of baseline MoCA, whereas motor prediction was strongly dependent on baseline UPDRS3. External validation preserved high NPVs (cognitive: 0.908 [0.872–0.940]; motor: 0.863 [0.818–0.901]). Incorporating first-year trajectory slopes improved AUROC by approximately 5%, supporting a single follow-up visit as a practical refinement timepoint. Performance gains rapidly plateaued after inclusion of a small number of high-value features, indicating an early performance ceiling. Decision curve analysis suggested potential net benefit across selected threshold probabilities, but prospective evaluation in broader and more heterogeneous populations is required before clinical implementation.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"46 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral blood transcriptomic signature is associated with cognitive impairment and freezing of gait in Parkinson’s disease: a data-driven approach","authors":"Reeree Lee, Mincheol Park","doi":"10.1038/s41531-026-01527-0","DOIUrl":"https://doi.org/10.1038/s41531-026-01527-0","url":null,"abstract":"Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder with variable long-term outcomes. Blood-based biomarkers for prognostic prediction remain underdeveloped. We aimed to develop a peripheral blood transcriptomic signature for predicting long-term complications in PD using unsupervised data-driven methods. Using RNA sequencing data from 541 PD patients and 180 healthy controls from the Parkinson’s Progression Markers Initiative (PPMI), we employed weighted gene correlation network analysis (WGCNA) to identify disease-associated gene modules. Contrastive principal component analysis was applied to derive a pseudo-temporal (PT) trajectory score reflecting molecular disease progression. The prognostic value of PT scores was assessed through Cox regression for cognitive impairment, freezing of gait (FOG), wearing-off, and levodopa-induced dyskinesia. WGCNA identified two PD-associated co-expression modules enriched for immune/inflammatory pathways. PT scores derived from these modules showed significant correlations with cognitive, autonomic, and axial motor symptoms. In multivariable Cox regression, higher PT scores independently predicted cognitive impairment (HR = 7.31, P = 0.002) and FOG (HR = 3.43, P < 0.001), but not predominantly dopaminergic motor complications. These findings demonstrate that peripheral blood transcriptomic signatures capture aspects of PD pathophysiology that are not fully explained by nigrostriatal dopaminergic degeneration alone, serving as potential prognostic biomarkers for cognitive impairment and FOG.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"1 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148728964","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}