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BACKGROUND: Vascular growth followed by vessel specification is crucial for the establishment of a hierarchical blood vascular network. We have shown that TIE2 is required for vein development while little is known about its homologue TIE1 (tyrosine kinase with immunoglobulin-like and EGF [epithelial growth factor]-like domains 1) in this process. METHODS: We analyzed functions of TIE1 as well as its synergy with TIE2 in the regulation of vein formation by employing genetic mouse models targeting Tie1, Tek, and Nr2f2, together with in vitro cultured endothelial cells to decipher the underlying mechanism. RESULTS: Cardinal vein growth appeared normal in TIE1-deficient mice, whereas TIE2 deficiency altered the identity of cardinal vein endothelial cells with the aberrant expression of DLL4 (delta-like canonical Notch ligand 4). Interestingly, the growth of cutaneous veins, which was initiated at approximately embryonic day 13.5, was retarded in mice lack of TIE1. TIE1 deficiency disrupted the venous integrity, displaying increased sprouting angiogenesis and vascular bleeding. Abnormal venous sprouts with defective arteriovenous alignment were also observed in the mesenteries of Tie1-deleted mice. Mechanistically, TIE1 deficiency resulted in the decreased expression of venous regulators including TIE2 and COUP-TFII (chicken ovalbumin upstream promoter transcription factor, encoded by Nr2f2, nuclear receptor subfamily 2 group F member 2) while angiogenic regulators were upregulated. The alteration of TIE2 level by TIE1 insufficiency was further confirmed by the siRNA-mediated knockdown of Tie1 in cultured endothelial cells. Interestingly, TIE2 insufficiency also reduced the expression of TIE1. Combining the endothelial deletion of Tie1 with 1 null allele of Tek resulted in a progressive increase of vein-associated angiogenesis leading to the formation of vascular tufts in retinas, whereas the loss of Tie1 alone produced a relatively mild venous defect. Furthermore, the induced deletion of endothelial Nr2f2 decreased both TIE1 and TIE2. CONCLUSIONS: Findings from this study imply that TIE1 and TIE2, together with COUP-TFII, act in a synergistic manner to restrict sprouting angiogenesis during the development of venous system.
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Receptor de TIE-1 , Receptor TIE-2 , Camundongos , Animais , Receptor de TIE-1/genética , Receptor de TIE-1/metabolismo , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Células Endoteliais/metabolismo , Transdução de Sinais , VeiasRESUMO
Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.
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Doença de Parkinson , Humanos , Doença de Parkinson/genética , Doença de Parkinson/epidemiologia , Haplótipos , Mitocôndrias/genética , DNA Mitocondrial/genética , Progressão da Doença , CogniçãoRESUMO
BACKGROUND: Cognitive decline in Parkinson's disease (PD) is prevalent, insidious, and burdensome during the progression of the disease. OBJECTIVES: We aimed to find transcriptome-wide biomarkers in blood to predict cognitive decline and identify patients at high risk with cognitive impairment in PD. METHODS: We carried out joint modeling analysis to characterize transcriptome-wide longitudinal gene expression and its association with the progression of mild cognitive impairment (MCI) in PD patients. The average time-dependent area under the curves (AUCs) were used for evaluating the accuracy of the significant joint models. A cognitive survival score (CogSs) derived from joint model was leveraged to predict the occurrence of MCI. All predicting models were built in a discovery cohort with 272 patients and replicated in an independent cohort with 177 patients. RESULTS: We identified five longitudinal varied expression of transcripts that were significantly associated with MCI progression in patients with PD. The most significant transcript IGLC1 joint model accurately predicted the progression of MCI in PD patients in the discovery and replication cohorts (average time-dependent AUCs >0.82). The CogSs derived from the optimal IGLC1 joint model had a high accuracy at early study stage in both cohorts (AUC ≥0.91). CONCLUSIONS: Our transcriptome-wide joint modeling analysis uncovered five blood-based transcripts related to cognitive decline in PD. The joint models will serve as a useful resource for clinicians and researchers to screen PD patients with high risk of development of cognitive impairment and pave the path for Parkinson's personalized medicine. © 2022 International Parkinson and Movement Disorder Society.
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Disfunção Cognitiva , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/genética , Doença de Parkinson/psicologia , Testes Neuropsicológicos , Disfunção Cognitiva/genética , Disfunção Cognitiva/complicações , Área Sob a Curva , Biomarcadores , Progressão da DoençaRESUMO
BACKGROUND: Common genetic variance in apolipoprotein E (APOE), ß-glucocerebrosidase (GBA), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) has been linked to cognitive decline in Parkinson's disease (PD), although studies have yielded mixed results. OBJECTIVES: To evaluate the effect of genetic variants in APOE, GBA, MAPT, and SNCA on cognitive decline and risk of dementia in a pooled analysis of six longitudinal, non-selective, population-based cohorts of newly diagnosed PD patients. METHODS: 1002 PD patients, followed for up to 10 years (median 7.2 years), were genotyped for at least one of APOE-ε4, GBA mutations, MAPT H1/H2, or SNCA rs356219. We evaluated the effect of genotype on the rate of cognitive decline (Mini-Mental State Examanation, MMSE) using linear mixed models and the development of dementia (diagnosed using standardized criteria) using Cox regression; multiple comparisons were accounted for using Benjamini-Hochberg corrections. RESULTS: Carriers of APOE-ε4 (n = 281, 29.7%) and GBA mutations (n = 100, 10.3%) had faster cognitive decline and were at higher risk of progression to dementia (APOE-ε4, HR 3.57, P < 0.001; GBA mutations, HR 1.76, P = 0.001) than non-carriers. The risk of cognitive decline and dementia (HR 5.19, P < 0.001) was further increased in carriers of both risk genotypes (n = 23). No significant effects were observed for MAPT or SNCA rs356219. CONCLUSIONS: GBA and APOE genotyping could improve the prediction of cognitive decline in PD, which is important to inform the clinical trial selection and potentially to enable personalized treatment © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Disfunção Cognitiva , Demência , Doença de Parkinson , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Disfunção Cognitiva/genética , Demência/genética , Glucosilceramidase/genética , Humanos , Mutação/genética , Doença de Parkinson/complicações , Doença de Parkinson/genética , Doença de Parkinson/psicologiaRESUMO
BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society.
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Disfunção Cognitiva , Doença de Parkinson , Atividades Cotidianas , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Doença de Parkinson/epidemiologiaRESUMO
RNA modifications are dynamic chemical entities that expand the RNA lexicon and regulate RNA fate. The most abundant modification present in mRNAs, N6-methyladenosine (m6A), has been implicated in neurogenesis and memory formation. However, whether additional RNA modifications may be playing a role in neuronal functions and in response to environmental queues is largely unknown. Here we characterize the biochemical function and cellular dynamics of two human RNA methyltransferases previously associated with neurological dysfunction, TRMT1 and its homolog, TRMT1-like (TRMT1L). Using a combination of next-generation sequencing, LC-MS/MS, patient-derived cell lines and knockout mouse models, we confirm the previously reported dimethylguanosine (m2,2G) activity of TRMT1 in tRNAs, as well as reveal that TRMT1L, whose activity was unknown, is responsible for methylating a subset of cytosolic tRNAAla(AGC) isodecoders at position 26. Using a cellular in vitro model that mimics neuronal activation and long term potentiation, we find that both TRMT1 and TRMT1L change their subcellular localization upon neuronal activation. Specifically, we observe a major subcellular relocalization from mitochondria and other cytoplasmic domains (TRMT1) and nucleoli (TRMT1L) to different small punctate compartments in the nucleus, which are as yet uncharacterized. This phenomenon does not occur upon heat shock, suggesting that the relocalization of TRMT1 and TRMT1L is not a general reaction to stress, but rather a specific response to neuronal activation. Our results suggest that subcellular relocalization of RNA modification enzymes may play a role in neuronal plasticity and transmission of information, presumably by addressing new targets.
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Encéfalo/metabolismo , Núcleo Celular/metabolismo , Neuroblastoma/patologia , Neurônios/metabolismo , Frações Subcelulares/metabolismo , tRNA Metiltransferases/metabolismo , Animais , Feminino , Camundongos , Camundongos Knockout , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neurônios/citologia , tRNA Metiltransferases/genéticaRESUMO
INTRODUCTION: Variants in the GBA1 gene have been identified as a common risk factor for Parkinson's disease (PD). In addition to pathogenic mutations (those associated with Gaucher disease), a number of 'non-pathogenic' variants also occur at increased frequency in PD. Previous studies have reported that pathogenic variants adversely affect the clinical course of PD. The role of 'non-pathogenic' GBA1 variants on PD course is less clear. In this study, we report the effect of GBA1 variants in incident PD patients with long-term follow-up. METHODS: The study population consisted of patients in the Cambridgeshire Incidence of Parkinson's disease from General Practice to Neurologist and Parkinsonism: Incidence, Cognition and Non-motor heterogeneity in Cambridgeshire cohorts. Patients were grouped into non-carriers, carriers of 'non-pathogenic' GBA1 variants and carriers of pathogenic GBA1 mutations. Survival analyses for time to development of dementia, postural instability and death were carried out. Cox regression analysis controlling for potential confounders were used to determine the impact of GBA1 variants on these outcome measures. RESULTS: GBA1 variants were identified in 14.4% of patients. Pathogenic and 'non-pathogenic' GBA1 variants were associated with the accelerated development of dementia and a more aggressive motor course. Pathogenic GBA1 variants were associated with earlier mortality in comparison with non-carriers, independent of the development of dementia. DISCUSSION: GBA1 variants, including those not associated with Gaucher disease, are common in PD and result in a more aggressive disease course.
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Glucosilceramidase/genética , Mutação , Doença de Parkinson/genética , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/mortalidade , Taxa de SobrevidaRESUMO
BACKGROUND: Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied. OBJECTIVES: To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale. METHODS: We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes. RESULTS: Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. CONCLUSIONS: We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.
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Estudo de Associação Genômica Ampla , Doença de Parkinson/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Biomarcadores , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/psicologia , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Feminino , Glucosilceramidase/genética , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteínas de Transporte de Cátions Orgânicos/genética , Doença de Parkinson/psicologia , Fenótipo , Medição de RiscoRESUMO
RNA polymerase III is essential for the transcription of non-coding RNAs, including tRNAs. Mutations in the genes encoding its largest subunits are known to cause hypomyelinating leukodystrophies (HLD7) with pathogenetic mechanisms hypothesised to involve impaired availability of tRNAs. We have identified a founder mutation in the POLR3A gene that leads to aberrant splicing, a premature termination codon and partial deficiency of the canonical full-length transcript. Our clinical and imaging data showed no evidence of the previously reported white matter or cerebellar involvement; instead the affected brain structures included the striatum and red nuclei with the ensuing clinical manifestations. Our transcriptome-wide investigations revealed an overall decrease in the levels of Pol III-transcribed tRNAs and an imbalance in the levels of regulatory ncRNAs such as small nuclear and nucleolar RNAs (snRNAs and snoRNAs). In addition, the Pol III mutation was found to exert complex downstream effects on the Pol II transcriptome, affecting the general regulation of RNA metabolism.
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Corpo Estriado/patologia , Degeneração Neural/congênito , RNA Polimerase III/genética , Transcrição Gênica , Transcriptoma/genética , Adulto , Cerebelo/metabolismo , Cerebelo/patologia , Criança , Corpo Estriado/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neostriado/metabolismo , Neostriado/patologia , Degeneração Neural/genética , Degeneração Neural/patologia , Fenótipo , Splicing de RNA/genética , RNA de Transferência/genéticaRESUMO
OBJECTIVE: We hypothesized that specific mutations in the ß-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. RESULTS: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60-6.25) and a hastened decline in Mini-Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92-4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89-2.05) did not reach significance. INTERPRETATION: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into "high gear." These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674-685.
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Disfunção Cognitiva/genética , Progressão da Doença , Doença de Gaucher/genética , Glucosilceramidase/genética , Doença de Parkinson/genética , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/etiologia , Feminino , Doença de Gaucher/complicações , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicaçõesRESUMO
There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.
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Doença de Parkinson/genética , Doença de Parkinson/patologia , alfa-Sinucleína/sangue , alfa-Sinucleína/genética , Idoso , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Regulação da Expressão Gênica , Testes Genéticos , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Neuroimagem , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , RNA Mensageiro/metabolismo , Cintilografia , Índice de Gravidade de Doença , TropanosRESUMO
BACKGROUND: Adenosine-to-inosine (A-to-I) editing is the most common type of RNA editing in humans and the role of A-to-I RNA editing remains unclear in Parkinson's disease (PD). OBJECTIVE: We aimed to explore the potential causal association between A-to-I editing and PD, and to assess whether changes in A-to-I editing were associated with cognitive progression in PD. METHODS: The RNA-seq data from 380 PD patients and 178 healthy controls in the Parkinson's Progression Marker Initiative cohort was used to quantify A-to-I editing sites. We performed cis-RNA editing quantitative trait loci analysis and a two-sample Mendelian Randomization (MR) study by integrating genome-wide association studies to infer the potential causality between A-to-I editing and PD pathogenesis. The potential causal A-to-I editing sites were further confirmed by Summary-data-based MR analysis. Spearman's correlation analysis was performed to characterize the association between longitudinal A-to-I editing and cognitive progression in patients with PD. RESULTS: We identified 17 potential causal A-to-I editing sites for PD and indicated that genetic risk variants may contribute to the risk of PD through A-to-I editing. These A-to-I editing sites were located in genes NCOR1, KANSL1 and BST1. Moreover, we observed 57 sites whose longitudinal A-to-I editing levels correlated with cognitive progression in PD. CONCLUSIONS: We found potential causal A-to-I editing sites for PD onset and longitudinal changes of A-to-I editing were associated with cognitive progression in PD. We anticipate this study will provide new biological insights and drive the discovery of the epitranscriptomic role underlying Parkinson's disease.
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Doença de Parkinson , Humanos , Doença de Parkinson/genética , Estudo de Associação Genômica Ampla , Perfilação da Expressão Gênica , Locos de Características Quantitativas , Análise da Randomização MendelianaRESUMO
INTRODUCTION: A valid, reliable, accessible measurement for the early detection of cognitive decline in patients with Parkinson's disease (PD) is in urgent demand. The objective of the study is to assess the clinical utility of the MemTrax Memory Test in detecting cognitive impairment in patients with PD. METHODS: The MemTrax, a fast on-line cognitive screening tool based on continuous recognition task, and Montreal Cognitive Assessment (MoCA) were administered to 61 healthy controls (HC), 102 PD patients with normal cognition (PD-N), 74 PD patients with mild cognitive impairment (PD-MCI) and 52 PD patients with dementia (PD-D). The total percent correct (MTx- %C), average response time (MTx-RT), composite score (MTx-Cp) of MemTrax and the MoCA scores were comparatively analyzed. RESULTS: The MoCA scores were similar between HC and PD-N, however, MTx- %C and MTx-Cp were lower in PD-N than HC(p < 0.05). MTx- %C, MTx-Cp and the MoCA scores were significantly lower in PD-MCI versus PD-N and in PD-D versus PD-MCI (p ≤ 0.001), while MTx-RT was statistically longer in PD-D versus PD-MCI (p ≤ 0.001). For PD groups, the MemTrax performance correlated with the MoCA scores. To detect PD-MCI, the optimal MTx- %C and MTx-Cp cutoff were 75 % and 50.0, respectively. To detect PD-D, the optimal MTx- %C, MTx-RT and MTx-Cp cutoff were 69 %, 1.341s and 40.6, respectively. CONCLUSION: The MemTrax provides rapid, valid and reliable metrics for assessing cognition in PD patients which could be useful for identifying PD-MCI at early stage and monitoring cognitive function decline during the progression of disease.
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Disfunção Cognitiva , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Testes Neuropsicológicos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Cognição , Testes de Estado Mental e DemênciaRESUMO
Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinson's disease (PD) are urgently needed. In this study, we leverage the large-scale whole-blood total RNA-seq dataset from the Accelerating Medicine Partnership in Parkinson's Disease (AMP PD) program to identify PD-associated RNAs, including both known genes and novel circular RNAs (circRNA) and enhancer RNAs (eRNAs). There were 1,111 significant marker RNAs, including 491 genes, 599 eRNAs, and 21 circRNAs, that were first discovered in the PPMI cohort (FDR < 0.05) and confirmed in the PDBP/BioFIND cohorts (nominal p < 0.05). Functional enrichment analysis showed that the PD-associated genes are involved in neutrophil activation and degranulation, as well as the TNF-alpha signaling pathway. We further compare the PD-associated genes in blood with those in post-mortem brain dopamine neurons in our BRAINcode cohort. 44 genes show significant changes with the same direction in both PD brain neurons and PD blood, including neuroinflammation-associated genes IKBIP, CXCR2, and NFKBIB. Finally, we built a novel multi-omics machine learning model to predict PD diagnosis with high performance (AUC = 0.89), which was superior to previous studies and might aid the decision-making for PD diagnosis in clinical practice. In summary, this study delineates a wide spectrum of the known and novel RNAs linked to PD and are detectable in circulating blood cells in a harmonized, large-scale dataset. It provides a generally useful computational framework for further biomarker development and early disease prediction.
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RATIONALE: MicroRNAs (miRNAs) are key regulators of vascular development and diseases. The function and underlying mechanism of endothelial miRNAs have not been fully defined. OBJECTIVE: To investigate the role of endothelial miR-126 in zebrafish vascular development. METHODS AND RESULTS: Two homologs of miR-126, miR-126a (namely miR-126 in previous literature) and miR-126b, with only 1 nucleotide difference in their mature sequences, were identified in zebrafish genome. In vitro analysis showed that both precursors could sufficiently produce mature functional miRNAs. Expression analyses by Northern blot and quantitative RT-PCR showed that both miR-126s accumulated significantly 12 hours after fertilization and were specifically expressed in endothelial cells of zebrafish. Inhibition of miR-126a or miR-126b with specific morpholinos caused cranial hemorrhage, and simultaneous inhibition of both miR-126s resulted in a pronounced hemorrhage in higher percentage of embryos. Bioinformatics prediction showed that the targets of miR-126a/b partially overlapped but essentially differed. p21-activated kinase1 (pak1) was identified as a novel target of miR-126a/b, and pak1 3' untranslated region was differently regulated by these 2 miRNAs. Quantitative RT-PCR, in situ hybridization, and Western blot analyses showed that the level of pak1 was reduced when miR-126a/b were overexpressed. Notably, pak1 expression in endothelial cells was increased when miR-126a/b were knocked down. Furthermore, overexpression of the active form of human pak1 caused cranial hemorrhage, and knockdown pak1 effectively rescued the hemorrhage caused by inhibiting miR-126a/b. CONCLUSIONS: Two functional endothelial cell-specific miRNAs, miR-126a and miR-126b, synergistically regulate zebrafish vascular integrity, and pak1 is a critical target of miR-126a/b in vascular development.
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Endotélio Vascular/metabolismo , MicroRNAs/metabolismo , Peixe-Zebra/metabolismo , Quinases Ativadas por p21/metabolismo , Animais , Desenvolvimento Embrionário/genética , Desenvolvimento Embrionário/fisiologia , Endotélio Vascular/embriologia , Hemorragias Intracranianas/genética , Hemorragias Intracranianas/metabolismo , MicroRNAs/genética , Modelos Animais , Peixe-Zebra/embriologiaRESUMO
BACKGROUND: The motor impairment in Parkinson's disease (PD) can be managed but effective treatments for stopping or slowing the disease process are lacking. The advent of transcriptomics studies in PD shed light on the development of promising measures to predict disease progression and discover novel therapeutic strategies. OBJECTIVE: To reveal the potential role of transcripts in the motor impairment progression of patients with PD via transcriptome analysis. METHODS: We separately analyzed the differentially expressed genes (DEGs) between PD cases and healthy controls in two cohorts using whole blood bulk transcriptome data. Based on the intersection of DEGs, we established a prognostic signature by regularized regression and Cox proportional hazards analysis. We further performed immune cell analysis and single-cell RNA sequencing analysis to study the biological features of this signature. RESULTS: We identified a two-gene-based prognostic signature that links to PD motor progression and the two-gene signature-derived risk score was associated with several types of immune cells in blood. Notably, the fraction of neutrophils increased 5% and CD4+ T cells decreased 7% in patients with high-risk scores compared to that in patients with low-risk scores, suggesting these two types of immune cells might play key roles in the prognosis of PD. We also observed the downregulated genes in PD patients with high-risk scores that enriched in PD-associated pathways from iPSC-derived dopaminergic neurons single-cell RNA sequencing analysis. CONCLUSION: We identified a two-gene signature linked to the motor progression in PD, which provides new insights into the motor prognosis of PD.
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Doença de Parkinson , Humanos , Doença de Parkinson/genética , Perfilação da Expressão Gênica , Transcriptoma , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: Accessible measurements for the early detection of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) are urgently needed to address the increasing prevalence of AD. OBJECTIVE: To determine the benefits of a composite MemTrax Memory Test and AD-related blood biomarker assessment for the early detection of MCI-AD in non-specialty clinics. METHODS: The MemTrax Memory Test and Montreal Cognitive Assessment were administered to 99 healthy seniors with normal cognitive function and 101 patients with MCI-AD; clinical manifestation and peripheral blood samples were collected. We evaluated correlations between the MemTrax Memory Test and blood biomarkers using Spearman's rank correlation analyses and then built discrimination models using various machine learning approaches that combined the MemTrax Memory Test and blood biomarker results. The models' performances were assessed according to the areas under the receiver operating characteristic curve. RESULTS: The MemTrax Memory Test and Montreal Cognitive Assessment areas under the curve for differentiating patients with MCI-AD from the healthy controls were similar. The MemTrax Memory Test strongly correlated with phosphorylated tau 181 and amyloid-ß42/40. The area under the curve for the best composite MemTrax Memory Test and blood biomarker model was 0.975 (95% confidence interval: 0.950-0.999). CONCLUSION: Combining MemTrax Memory Test and blood biomarker results is a promising new technique for the early detection of MCI-AD.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/psicologia , Proteínas tau , Biomarcadores , Diagnóstico Precoce , Peptídeos beta-AmiloidesRESUMO
Background: Immune checkpoint inhibitors have been successfully used in a variety of tumors, however, the efficacy of immune checkpoint blockade therapy for patients with glioma is limited. In this study, we tried to clarify gene expression signatures related to the prognosis of gliomas and construct a signature to predict the survival of patients with gliomas. Methods: Calcium-related differential expressed genes (DEGs) between gliomas and normal brain tissues were comprehensively analyzed in two independent databases. Univariate, multivariate Cox regression analysis and proportional hazards model were used to identify the prognostic of calcium-related risk score signature. The CIBERSORT algorithm and association analysis were carried out to evaluate the relationship between calcium-related signature and characteristic clinical features, tumor-infiltrating immune cell signatures as well as immune checkpoint molecules in glioma. A nomogram model was developed for predicting the overall survival for patients with gliomas. Results: We found the intersection of 415 DEGs between gliomas and normal brain tissues, and identified that an eighteen calcium-related gene panel was significantly enriched in these DEGs. A calcium-related signature derived risk score was developed to divide patients into high- and low-risk groups. Low levels of calcium-related gene expression in high-risk score cases were accompanied with worse outcomes of patients. Calcium-related risk scores were significantly associated with characteristic clinical features, immune infiltrating signatures of tumor microenvironment, and exhausted T cell markers including programmed cell death 1 (PD-1), lymphocyte activating 3 (LAG3), and T cell membrane protein 3 (TIM-3), which contribute to an adverse therapeutic effect of immunotherapy. Calcium-related signature risk score was considered as an independent prognostic parameter to predict the of overall survival of patients with gliomas in nomogram model. Conclusion: Our study demonstrated that calcium signaling pathway is highly associated with immunosuppression of gliomas and overall survival of patients. Targeting the calcium signaling pathway might be a new strategy to reverse the immunosuppressive microenvironment of gliomas and improve the efficacy of glioma immunotherapy.
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The relationship between fibrinogen and white matter hyperintensities (WMHs) are inconsistent. Whether there are different relationships between WMHs and fibrinogen in disparate subtypes of cerebral small vessel disease (CSVD) remains unknown. Here, we investigated the roles of plasma fibrinogen in sporadic CSVD (sCSVD) and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients. We performed a cross-sectional study that included 74 CSVD patients (19 CADASIL and 55 sporadic) and 74 age- and gender-matched healthy controls (HCs). Plasma fibrinogen was determined, and the severity of WMHs in CSVD patients was rated according to Fazekas scales. Univariate analysis and ordinal logistic regression were performed to evaluate the relationship between fibrinogen and the severity of WMHs in CSVD. Both CADASIL and sCSVD patients showed significantly higher plasma fibrinogen levels than HCs. No significant difference in the plasma fibrinogen level was observed between CADASIL and sCSVD. Univariate analysis and ordinal logistic regression indicated that fibrinogen is an independent risk factor for the severity of WMHs in CADASIL patients (odds ratio [OR] =1.064; 95% Confidence interval (CI, 1.004-1.127); p =0.037). However, age (odds ratio [OR] =1.093; 95% CI (1.033-1.156); P = 0.002), but not fibrinogen (odds ratio [OR] =1.004; 95% CI (0.997-1.011); P=0.262), is an independent risk factor for the severity of WMHs in sCSVD patients. Our results suggest that high levels of plasma fibrinogen are associated with the severity of WMHs in CADASIL but not in sCSVD patients, indicating that the role of fibrinogen may be different in disparate subtypes of CSVD. A better understanding of fibrinogen may yield insights into the pathogenesis of CSVD.