NPJ Parkinson's Disease最新文献

Magnetic resonance imaging and circulating molecular testing are potential methods for diagnosing and treating Parkinson’s disease (PD). However, their relationships remain insufficiently studied. Using genome-wide association summary statistics, we found in the general population a genetic negative correlation between white matter tract mean diffusivity and PD (-0.17 < Rg < -0.11, p < 0.05), and a positive correlation with intracellular volume fraction (0.12 < Rg < 0.2, p < 0.05). Additionally, 1345 circulating genes causally linked with white matter tract diffusivity were enriched for muscle physiological abnormalities (padj < 0.05). Notable genes, including LRRC37A4P (effect size = 15.7, p = 1.23E-55) and KANSL1-AS1 (effect size = -15.3, p = 1.13E-52), were directly associated with PD. Moreover, 23 genes were found linked with genetically correlated PD-IDP pairs (PPH4 > 0.8), including SH2B1 and TRIM10. Our study bridges the gap between molecular genetics, neuroimaging, and PD pathology, and suggests novel targets for diagnosis and treatment.

Association of prodromal Parkinson’s disease (PD) with risk of PD and risk of mortality in individuals with PD warrant investigation through large-scale prospective study. We included 501,475 participants without PD at baseline. Eight prodromal features were measured. Incident PD cases were identified via hospital admission, death register, and self-report. Cox regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariable-adjusted HRs_{3+vs.0 prodromal PD features} and 95%CIs were 3.12 (2.58–3.78) for men and 2.71 (2.11–3.47) for women. Prodromal PD predicted only PD onset occurred during the first 6 years of follow-up (HR_{3+vs.0 prodromal features} = 10.5; 95% CI: 8.60–12.9), but not after 6 years (HR = 1.00; 95%CI: 0.76-1.32). The presence of prodromal PD conferred a higher risk of mortality among participants with PD. Having prodromal PD were associated with higher probability of developing PD in short-term and higher risk of mortality among individuals with PD.

The dysfunction of dopaminergic (DA) neurons is central to Parkinson’s disease. Distinct synaptic vesicle (SV) populations, differing in neurotransmitter content (dopamine vs. glutamate), may vary due to differences in trafficking and exocytosis. However, the structural organization of these vesicles remains unclear. In this study, we examined axonal varicosities in human iPSC-derived DA and glutamatergic neurons (i³Neurons). i³Neurons primarily contained small, clear SVs (40–50 nm), whereas DA neurons contained larger, pleiomorphic vesicles including dense core and empty vesicles, in addition to the classical SVs. VMAT2-positive vesicles in DA neurons, which load dopamine, were spatially segregated from VGLUT1/2-positive vesicles in an SV-like reconstitution system. These vesicles also colocalized with SV markers (e.g., VAMP2, SV2C), and can be clustered by synapsin. Moreover, DA axonal terminals in mouse striata showed similar vesicle pool diversity. These findings reveal structural differences in DA neurons’ vesicles, highlighting iPSC-derived neurons as effective models for studying presynaptic structures.

Chronic neuroinflammation with sustained microglial activation occurs in Parkinson’s disease (PD), yet the mechanisms and exact contribution of these cells to the neurodegeneration remains poorly understood. In this study, we induced progressive dopaminergic neuron loss in mice via rAAV-hSYN injection to cause the neuronal expression of α-synuclein, which produced neuroinflammation and behavioral alterations. We administered PLX5622, a colony-stimulating factor 1 receptor inhibitor, for 3 weeks prior to rAAV-hSYN injection, maintaining it for 8 weeks to eliminate microglia. This chronic treatment paradigm prevented the development of motor deficits and concomitantly preserved dopaminergic neuron cell and weakened α-synuclein phosphorylation. Gene expression profiles related to extracellular matrix (ECM) remodeling were increased after microglia depletion in PD mice, which were further validated on protein level. We demonstrated that microglia exert adverse effects during α-synuclein-overexpression-induced neuronal lesion formation, and their depletion remodels ECM and aids recovery following insult.

The risk of Parkinson’s disease (PD) associated with farming has received considerable attention, in particular for pesticide exposure. However, data on PD risk associated with specific farming activities is lacking. We aimed to explore whether specific farming activities exhibited a higher risk of PD than others among the entire French farm manager (FM) population. A secondary analysis of real-world administrative insurance claim data and electronic health/medical records (TRACTOR project) was conducted to estimate PD risk for 26 farming activities using data mining. PD cases were identified through chronic disease declarations and antiparkinsonian drug claims. There were 8845 PD cases among 1,088,561 FMs. The highest-risk group included FMs engaged in pig farming, cattle farming, truck farming, fruit arboriculture, and crop farming, with mean hazard ratios (HRs) ranging from 1.22 to 1.67. The lowest-risk group included all activities involving horses and small animals, as well as gardening, landscaping and reforestation companies (mean HRs: 0.48–0.81). Our findings represent a preliminary work that suggests the potential involvement of occupational risk factors related to farming in PD onset and development. Future research focusing on farmers engaged in high-risk farming activities will allow to uncover potential occupational factors by better characterizing the farming exposome, which could improve PD surveillance among farmers.

Parkinson’s disease arises from the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms such as akinesia, rigidity, and tremor at rest. The non-motor component of Parkinson’s disease includes increased neuropathic pain, the prevalence of which is 4 to 5 times higher than the general rate. By studying a mouse model of Parkinson’s disease induced by 6-hydroxydopamine, we assessed the impact of dopamine depletion on pain modulation. Mice exhibited mechanical hypersensitivity associated with hyperexcitability of neurons in the dorsal horn of the spinal cord (DHSC). Serotonin (5-HT) levels increased in the spinal cord, correlating with reduced tyrosine hydroxylase (TH) immunoreactivity in the nucleus raphe magnus (NRM) and increased excitability of 5-HT neurons. Selective optogenetic inhibition of 5-HT neurons attenuated mechanical hypersensitivity and reduced DHSC hyperexcitability. In addition, the blockade of 5-HT_2A and 5-HT₃ receptors reduced mechanical hypersensitivity. These results reveal, for the first time, that PD-like dopamine depletion triggers spinal-mediated mechanical hypersensitivity, associated with serotonergic hyperactivity in the NRM, opening up new therapeutic avenues for Parkinson’s disease-associated pain targeting the serotonergic systems.

Data on gait parameters during real-life activities and home rehabilitation programs for Persons with Parkinson’s disease (PwPDs) are scarce. Although cueing has been shown to improve their gait in laboratory conditions, few studies have applied this technique in at-home rehabilitation programs. Our study aimed to explore the use of a real-time synchronized beat-step music program for at-home rehabilitation. We conducted a 1-month outdoor gait rehabilitation program called BeatPark (30 min/day, 5 days/week), with 25 PwPDs, using real-time synchronized, cued, music, and measurements through the BeatMove application. We demonstrated that real-world walking with BeatMove exhibited improved gait parameters both within and across sessions. These improvements were further confirmed by the Six-Minute Walk Test conducted in silence in the laboratory before and after the program. Measures in real life are unique tools to enhance rehabilitation programs. Future research incorporating a control group will be essential to fully validate these encouraging findings.

This study explores the effect of risk factors on the progression of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) to α-synucleinopathies in a Chinese cohort. Patients with iRBD were enrolled and assessed for environmental factors and lifestyle using standardized structured questionnaires at baseline. All patients were prospectively followed for phenoconversion monitoring. The cumulative incidence was estimated using survival analysis. Of 155 iRBD enrolled in the cohort, follow-up information was available in 141 patients. The phenoconversion rate was 16.3% after 3 years, 27.6% after 5 years, and 57.2% after 10 years. Eighteen participants converted within 3 years, 27 converted within 5 years, and 36 converted within 10 years. IRBD with positive family history of parkinsonism had an increased risk of being converted to α-synucleinopathies, while tea drinking was associated with a decreased phenoconversion risk. Our findings shed light on a potential application of tea drinking in modifying iRBD progression.

Loss-of-function mutations in PARK7, encoding for DJ-1, can lead to early onset Parkinson’s disease (PD). In mice, Park7 deletion leads to dopaminergic deficits during aging, and increased sensitivity to oxidative stress. However, the severity of the reported phenotypes varies. To understand the early molecular changes upon loss of DJ-1, we performed transcriptomic profiling of midbrain sections from young mice. While at 3 months the transcriptomes of both male and female mice were unchanged compared to their wildtype littermates, an extensive deregulation was observed in 8 month-old males. The affected genes are involved in processes like focal adhesion, extracellular matrix interaction, and epithelial-to-mesenchymal transition (EMT), and enriched for primary target genes of NRF2. Consistently, the antioxidant response was altered specifically in the midbrain of male DJ-1 deficient mice. Many of the misregulated genes are known target genes of estrogen and retinoic acid signaling and show sex-specific expression in wildtype mice. Depletion of DJ-1 or NRF2 in male primary astrocytes recapitulated many of the in vivo changes, including downregulation of CYP1B1, an enzyme involved in estrogen and retinoic acid metabolism. Interestingly, knock-down of CYP1B1 led to gene expression changes in focal adhesion and EMT in primary male astrocytes. Finally, male iPSC-derived astrocytes with loss of function mutation in the PARK7 gene also showed changes in the EMT pathway and NRF2 target genes. Taken together, our data indicate that loss of Park7 leads to sex-specific gene expression changes through astrocytic alterations in the NRF2-CYP1B1 axis, suggesting higher sensitivity of males to loss of DJ-1.

Metabotropic glutamate (mGlu) receptors are candidate drug targets for therapeutic intervention in Parkinson’s disease (PD). Here we focused on mGlu3, a receptor subtype involved in synaptic regulation and neuroinflammation. mGlu3^−/− mice showed an enhanced nigro-striatal damage and microglial activation in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Expression of genes encoding anti-inflammatory proteins and neuroprotective factors was reduced in the striatum of MPTP-treated mGlu3^−/− mice. We also examined polymorphic variants of GRM3 (the mGlu3 receptor encoding gene) in 723 PD patients and 826 healthy controls. Two GRM3 haplotypes were associated with PD, and gene variants correlated with motor and non-motor signs. Interestingly, PD patients carrying each of the two haplotypes showed an impaired cortical plasticity in the paired associated stimulation paradigm of magnetic transcranial stimulation. These findings suggest that mGlu3 receptors are neuroprotective in mouse models of parkinsonism and shape mechanisms of cortical plasticity in PD.