NPJ Parkinson's Disease最新文献

{"title":"Towards a methodological uniformization of environmental risk studies in Parkinson’s disease","authors":"B. L. Santos-Lobato","doi":"10.1038/s41531-024-00709-y","DOIUrl":"https://doi.org/10.1038/s41531-024-00709-y","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140690606","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":"Resequencing the complete SNCA locus in Indian patients with Parkinson’s disease","authors":"Asha Kishore, Marc Sturm, Kanchana Soman Pillai, Christopher Hakkaart, Divya Kalikavil Puthanveedu, Madhusoodanan Urulangodi, Syam Krishnan, Ashwin Ashok Kumar Sreelatha, Roopa Rajan, Pramod Kumar Pal, Ravi Yadav, Gangadhara Sarma, Nicolas Casadei, Thomas Gasser, Peter Bauer, Olaf Riess, Manu Sharma","doi":"10.1038/s41531-024-00676-4","DOIUrl":"https://doi.org/10.1038/s41531-024-00676-4","url":null,"abstract":"<p>The genetic loci implicated in familial Parkinson’s disease (PD) have limited generalizability to the Indian PD population. We tested mutations and the frequency of known mutations in the <i>SNCA</i> gene in a PD cohort from India. We selected 298 PD cases and 301 age-matched controls for targeted resequencing (before QC), along with 363 PD genomes of Indian ancestry and 1029 publicly available whole genomes from India as healthy controls (IndiGenomes), to determine the frequency of monogenic <i>SNCA</i> mutations. The raw sequence reads were analyzed using an in-house analysis pipeline, allowing the detection of small variants and structural variants using Manta. The in-depth analysis of the <i>SNCA</i> locus did not identify missense or structural variants, including previously identified <i>SNCA</i> mutations, in the Indian population. The familial forms of <i>SNCA</i> gene variants do not play a major role in the Indian PD population and this warrants further research in the under-represented population.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140556832","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":"Grey matter networks in women and men with dementia with Lewy bodies","authors":"Annegret Habich, Javier Oltra, Christopher G. Schwarz, Scott A. Przybelski, Ketil Oppedal, Anna Inguanzo, Frédéric Blanc, Afina W. Lemstra, Jakub Hort, Eric Westman, Barbara Segura, Carme Junque, Val J. Lowe, Bradley F. Boeve, Dag Aarsland, Thomas Dierks, Kejal Kantarci, Daniel Ferreira","doi":"10.1038/s41531-024-00702-5","DOIUrl":"https://doi.org/10.1038/s41531-024-00702-5","url":null,"abstract":"<p>Sex differences permeate many aspects of dementia with Lewy bodies (DLB), yet sex differences in patterns of neurodegeneration in DLB remain largely unexplored. Here, we test whether grey matter networks differ between sexes in DLB and compare these findings to sex differences in healthy controls. In this cross-sectional study, we analysed clinical and neuroimaging data of patients with DLB and cognitively healthy controls matched for age and sex. Grey matter networks were constructed by pairwise correlations between 58 regional volumes after correction for age, intracranial volume, and centre. Network properties were compared between sexes and diagnostic groups. Additional analyses were conducted on <i>w</i>-scored data to identify DLB-specific sex differences. Data from 119 (68.7 ± 8.4 years) men and 45 women (69.9 ± 9.1 years) with DLB, and 164 healthy controls were included in this study. Networks of men had a lower nodal strength compared to women. In comparison to healthy women, the grey matter networks of healthy men showed a higher global efficiency, modularity, and fewer modules. None of the network measures showed significant sex differences in DLB. Comparing DLB patients with healthy controls revealed global differences in women and more local differences in men. Modular analyses showed a more distinct demarcation between cortical and subcortical regions in men compared with women. While topologies of grey matter networks differed between sexes in healthy controls, those sex differences were diluted in DLB patients. These findings suggest a disease-driven convergence of neurodegenerative patterns in women and men with DLB, which may inform precision medicine in DLB.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550541","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":"GUCY2C signaling limits dopaminergic neuron vulnerability to toxic insults","authors":"Lara Cheslow, Matthew Byrne, Jessica S. Kopenhaver, Lorraine Iacovitti, Richard J. Smeyne, Adam E. Snook, Scott A. Waldman","doi":"10.1038/s41531-024-00697-z","DOIUrl":"https://doi.org/10.1038/s41531-024-00697-z","url":null,"abstract":"<p>Mitochondrial dysfunction and reactive oxygen species (ROS) accumulation within the substantia nigra pars compacta (SNpc) are central drivers of dopaminergic (DA) neuron death in Parkinson’s disease (PD). Guanylyl cyclases and their second messenger cyclic (c)GMP support mitochondrial function, protecting against ROS and promoting cell survival in several tissues. However, the role of the guanylyl cyclase-cGMP axis in defining the vulnerability of DA neurons in the SNpc in PD remains unclear, in part due to the challenge of manipulating cGMP levels selectively in midbrain DA neurons. In that context, guanylyl cyclase C (GUCY2C), a receptor primarily expressed by intestinal epithelial cells, was discovered recently in midbrain DA neurons. Here, we demonstrate that GUCY2C promotes mitochondrial function, reducing oxidative stress and protecting DA neurons from degeneration in the 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) mouse model. GUCY2C is overexpressed in the SNpc in PD patients and in mice treated with MPTP, possibly reflecting a protective response to oxidative stress. Moreover, cGMP signaling protects against oxidative stress, mitochondrial impairment, and cell death in cultured DA neurons. These observations reveal a previously unexpected role for the GUCY2C-cGMP signaling axis in controlling mitochondrial dysfunction and toxicity in SNpc DA neurons, highlighting the therapeutic potential of targeting DA neuron GUCY2C to prevent neurodegeneration in PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550470","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":"Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutation","authors":"Quyen B. Do, Humaira Noor, Ricardo Marquez-Gomez, Kaitlyn M. L. Cramb, Bryan Ng, Ajantha Abbey, Naroa Ibarra-Aizpurua, Maria Claudia Caiazza, Parnaz Sharifi, Charmaine Lang, Dayne Beccano-Kelly, Jimena Baleriola, Nora Bengoa-Vergniory, Richard Wade-Martins","doi":"10.1038/s41531-024-00694-2","DOIUrl":"https://doi.org/10.1038/s41531-024-00694-2","url":null,"abstract":"<p>Understanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson’s disease (PD) given the architecture of the basal ganglia. Here, we developed a custom three-chambered microfluidic platform and established a cortico-striato-nigral microcircuit partially recapitulating the striatal presynaptic landscape in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, cortical glutamatergic projections facilitated MSN synaptic activity, and dopaminergic transmission enhanced maturation of MSNs in vitro. Replacement of wild-type iPSC-derived dopamine neurons (iPSC-DaNs) in the striatal microcircuit with those carrying the PD-related <i>GBA-N370S</i> mutation led to a depolarisation of resting membrane potential and an increase in rheobase in iPSC-MSNs, as well as a reduction in both voltage-gated sodium and potassium currents. Such deficits were resolved in late microcircuit cultures, and could be reversed in younger cultures with antagonism of protein kinase A activity in iPSC-MSNs. Taken together, our results highlight the unique utility of modelling striatal neurons in a modular physiological circuit to reveal mechanistic insights into <i>GBA1</i> mutations in PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140547575","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":"Predictors of stress resilience in Parkinson’s disease and associations with symptom progression","authors":"Anouk van der Heide, Lisanne J. Dommershuijsen, Lara M. C. Puhlmann, Raffael Kalisch, Bastiaan R. Bloem, Anne E. M. Speckens, Rick C. Helmich","doi":"10.1038/s41531-024-00692-4","DOIUrl":"https://doi.org/10.1038/s41531-024-00692-4","url":null,"abstract":"<p>People with Parkinson’s disease (PD) are sensitive to effects of long-term stress, but might differ in stress resilience, i.e. the ability to maintain mental health despite adversity. It is unclear whether stress resilience in PD is predominantly determined by dopamine deficiency, psychosocial factors, or both. In PD animal models, chronic stressors accelerate disease progression, but evidence in humans is lacking. Our objectives were to (1) distinguish stressor-reactive from resilient PD patients, (2) identify resilience factors, and (3) compare symptom progression between stressor-reactive and resilient patients. We conducted a longitudinal survey in Personalized Parkinson Project participants (<i>N</i> = 350 PD). We used the COVID-19 pandemic as a model of a stressor, aligned in time for the entire cohort. COVID-19-related stressors, perceived stress, and PD symptoms were assessed at 11 timepoints (April-October 2020). Both pre-COVID and in-COVID clinical assessments were available. We quantified stressor-reactivity as the residual between actual and predicted perceived stress relative to COVID-19-related stressors, and modeled trajectories of stressor-reactivity across timepoints. We explored pre-COVID predictors of 6-month average stressor-reactivity, and tested whether stressor-reactivity was prospectively associated with one-year clinical progression rates. Latent class trajectory models distinguished patients with high (<i>N</i> = 123) or low (<i>N</i> = 227) stressor-reactivity. Pre-existing anxiety, rumination and non-motor symptom severity predicted high stressor-reactivity (risk factors), whereas quality of life, social support, positive appraisal style and cognitive abilities predicted low stressor-reactivity (resilience factors). PD-specific factors, e.g. disease duration, motor severity, and levodopa use, did not predict stressor-reactivity. The COVID-19 pandemic did not accelerate disease progression, but worsened depressive symptoms in stressor-reactive PD patients.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140545227","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":"Elevated α-synuclein levels inhibit mitophagic flux","authors":"Inge Kinnart, Liselot Manders, Thibaut Heyninck, Dorien Imberechts, Roman Praschberger, Nils Schoovaerts, Catherine Verfaillie, Patrik Verstreken, Wim Vandenberghe","doi":"10.1038/s41531-024-00696-0","DOIUrl":"https://doi.org/10.1038/s41531-024-00696-0","url":null,"abstract":"<p>The pathogenic effect of <i>SNCA</i> gene multiplications indicates that elevation of wild-type α-synuclein levels is sufficient to cause Parkinson’s disease (PD). Mitochondria have been proposed to be a major target of α-synuclein-induced damage. PINK1/parkin/DJ-1-mediated mitophagy is a defense strategy that allows cells to selectively eliminate severely damaged mitochondria. Here, we quantified mitophagic flux and non-mitochondrial autophagic flux in three models of increased α-synuclein expression: 1/<i>Drosophila melanogaster</i> that transgenically express human wild-type and mutant α-synuclein in flight muscle; 2/human skin fibroblasts transfected with α-synuclein or β-synuclein; and 3/human induced pluripotent stem cell (iPSC)-derived neurons carrying an extra copy of wild-type <i>SNCA</i> under control of a doxycycline-inducible promoter, allowing titratable α-synuclein upregulation. In each model, elevated α-synuclein levels potently suppressed mitophagic flux, while non-mitochondrial autophagy was preserved. In human neurons, a twofold increase in wild-type α-synuclein was already sufficient to induce this effect. PINK1 and parkin activation and mitochondrial translocation of DJ-1 after mitochondrial depolarization were not affected by α-synuclein upregulation. Overexpression of the actin-severing protein cofilin or treatment with CK666, an inhibitor of the actin-related protein 2/3 (Arp2/3) complex, rescued mitophagy in neurons with increased α-synuclein, suggesting that excessive actin network stabilization mediated the mitophagy defect. In conclusion, elevated α-synuclein levels inhibit mitophagic flux. Disruption of actin dynamics may play a key role in this effect.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140538704","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":"Social isolation and the risk of Parkinson disease in the UK biobank study","authors":"Tingting Geng, Yaqi Li, Yinshun Peng, Xiao Chen, Xinming Xu, Jian Wang, Liang Sun, Xiang Gao","doi":"10.1038/s41531-024-00700-7","DOIUrl":"https://doi.org/10.1038/s41531-024-00700-7","url":null,"abstract":"<p>Parkinson disease (PD) has become one of the most rapidly growing causes of disability among the older population and social isolation is a major concern in the PD community. However, the relationship between social isolation and future risk of PD remains unclear. This study included 192,340 participants aged 60 or older who were free of dementia and PD at baseline from the UK Biobank study. Social isolation was measured using a composite score derived from three questions on number in household, frequency of friend/family visits, and leisure/social activities. Incident PD cases were identified through electronic health records. Multivariable-adjusted Cox regression models were used to compute the hazard ratio (HR) and 95% confidence interval (CI). Among the 192,340 participants (mean [standard deviation] age, 64.2 [2.9] years; 103,253 [53.7%] women), 89,075 (46.3%) participants were in the least isolated group and 26,161 (13.6%) were in the most isolated group. Over a median follow-up of 12.5 years, 2048 incident PD cases were documented. Compared to the least isolated group, the multivariable-adjusted HRs (95% CIs) for PD were 1.00 (0.91−1.10) for the moderately isolated group and 1.19 (1.05−1.36) for the most isolated group (<i>P</i>-_trend = 0.04). The observed association was independent of the genetic susceptibility to PD and consistent in subgroup analyses. Social isolation was associated with a higher risk of PD regardless of genetic risk. Our findings highlighted the importance of developing screening and intervention strategies for social isolation among older adults to reduce the risk of PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140538627","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":"Gut microbiome is not associated with mild cognitive impairment in Parkinson’s disease","authors":"Velma T. E. Aho, Matthias Klee, Zied Landoulsi, Anna Heintz-Buschart, Lukas Pavelka, Anja K. Leist, Rejko Krüger, Patrick May, Paul Wilmes","doi":"10.1038/s41531-024-00687-1","DOIUrl":"https://doi.org/10.1038/s41531-024-00687-1","url":null,"abstract":"<p>Gut microbiome differences between people with Parkinson’s disease (PD) and control subjects without Parkinsonism are widely reported, but potential alterations related to PD with mild cognitive impairment (MCI) have yet to be comprehensively explored. We compared gut microbial features of PD with MCI (<i>n</i> = 58) to cognitively unimpaired PD (<i>n</i> = 60) and control subjects (<i>n</i> = 90) with normal cognition. Our results did not support a specific microbiome signature related to MCI in PD.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140533938","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":"Modulation of subthalamic beta oscillations by movement, dopamine, and deep brain stimulation in Parkinson’s disease","authors":"Varvara Mathiopoulou, Roxanne Lofredi, Lucia K. Feldmann, Jeroen Habets, Natasha Darcy, Wolf-Julian Neumann, Katharina Faust, Gerd-Helge Schneider, Andrea A. Kühn","doi":"10.1038/s41531-024-00693-3","DOIUrl":"https://doi.org/10.1038/s41531-024-00693-3","url":null,"abstract":"<p>Subthalamic beta band activity (13–35 Hz) is known as a real-time correlate of motor symptom severity in Parkinson’s disease (PD) and is currently explored as a feedback signal for closed-loop deep brain stimulation (DBS). Here, we investigate the interaction of movement, dopaminergic medication, and deep brain stimulation on subthalamic beta activity in PD patients implanted with sensing-enabled, implantable pulse generators. We recorded subthalamic activity from seven PD patients at rest and during repetitive movements in four conditions: after withdrawal of dopaminergic medication and DBS, with medication only, with DBS only, and with simultaneous medication and DBS. Medication and DBS showed additive effects in improving motor performance. Distinct effects of each therapy were seen in subthalamic recordings, with medication primarily suppressing low beta activity (13–20 Hz) and DBS being associated with a broad decrease in beta band activity (13–35 Hz). Movement suppressed beta band activity compared to rest. This suppression was most prominent when combining medication with DBS and correlated with motor improvement within patients. We conclude that DBS and medication have distinct effects on subthalamic beta activity during both rest and movement, which might explain their additive clinical effects as well as their difference in side-effect profiles. Importantly, subthalamic beta activity significantly correlated with motor symptoms across all conditions, highlighting its validity as a feedback signal for closed-loop DBS.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":8.7,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140349568","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}