A recent multicenter study demonstrated that two variants of LRRK2, S1647T and R1398H, are associated with sporadic Parkinson＇s disease. The present study analyzed LRRK2 gene polymorphisms of S1647T and R1398H, demon...A recent multicenter study demonstrated that two variants of LRRK2, S1647T and R1398H, are associated with sporadic Parkinson＇s disease. The present study analyzed LRRK2 gene polymorphisms of S1647T and R1398H, demonstrating that the LRRK2 gene polymorphism S1647T variant is a risk factor for Parkinson＇s disease in a Chinese Han population. However, the R1398H variant did not influence the risk for Parkinson＇s disease. In addition, there was no difference in clinical symptoms of Parkinson＇s disease patients with various genotypes. Results showed that the LRRK2 S1647T variant was associated with an increased risk for developing early-onset Parkinson＇s disease in a Chinese Hart population. In addition, there was no correlation between LRRK2 S1647T, R1398H variants and G2385R, R1628P variants in Parkinson＇s disease patients.展开更多
Dysfunctional autophagy often occurs during the development of neurodegenerative diseases,such as Parkinson’s disease,Huntington’s disease,and Alzheimer’s disease.The purinergic P2X4 receptor is an ATP-gated ion ch...Dysfunctional autophagy often occurs during the development of neurodegenerative diseases,such as Parkinson’s disease,Huntington’s disease,and Alzheimer’s disease.The purinergic P2X4 receptor is an ATP-gated ion channel that is widely expressed in the microglia,astrocytes,and neurons of the central and peripheral nervous systems.P2X4R is involved in the regulation of cellular excitability,synaptic transmission,and neuroinflammation.However,the role played by P2X4R in Parkinson’s disease remains poorly understood.Rat models of Parkinson’s disease were established by injecting 6-hydroxydopamine into the substantia nigra pars compacta.P2X4R-targeted small interfering RNA(siRNA)was injected into the same area 1 week before injury induction to inhibit the expression of the P2X4 receptor.The results showed that the inhibition of P2X4 receptor expression in Parkinson’s disease model rats reduced the rotation behavior induced by apomorphine treatment,increased the latency on the rotarod test,and upregulated the expression of tyrosine hydroxylase,brain-derived neurotrophic factor,LC3-II/LC3-I,Beclin-1,and phosphorylated tropomyosin receptor kinase B(TrkB)in brain tissue,while simultaneously reducing p62 levels.These findings suggest that P2X4 receptor activation might inhibit neuronal autophagy through the regulation of the brain-derived neurotrophic factor/TrkB signaling pathway,leading to dopaminergic neuron damage in the substantia nigra and the further inhibition of P2X4 receptor-mediated autophagy.These results indicate that P2X4 receptor might serve as a potential novel target for the treatment of Parkinson’s disease.This study was approved by the Animal Ethics Committee of Affiliated Hospital of Qingdao University(approval No.QYFYWZLL26119)on April 12,2016.展开更多
Brain radiomics can reflect the characteristics of brain pathophysiology.However,the value of T1-weighted images,quantitative susceptibility mapping,and R2*mapping in the diagnosis of Parkinson’s disease(PD)was under...Brain radiomics can reflect the characteristics of brain pathophysiology.However,the value of T1-weighted images,quantitative susceptibility mapping,and R2*mapping in the diagnosis of Parkinson’s disease(PD)was underestimated in previous studies.In this prospective study to establish a model for PD diagnosis based on brain imaging information,we collected high-resolution T1-weighted images,R2*mapping,and quantitative susceptibility imaging data from 171 patients with PD and 179 healthy controls recruited from August 2014 to August 2019.According to the inclusion time,123 PD patients and 121 healthy controls were assigned to train the diagnostic model,while the remaining 106 subjects were assigned to the external validation dataset.We extracted 1408 radiomics features,and then used data-driven feature selection to identify informative features that were significant for discriminating patients with PD from normal controls on the training dataset.The informative features so identified were then used to construct a diagnostic model for PD.The constructed model contained 36 informative radiomics features,mainly representing abnormal subcortical iron distribution(especially in the substantia nigra),structural disorganization(e.g.,in the inferior temporal,paracentral,precuneus,insula,and precentral gyri),and texture misalignment in the subcortical nuclei(e.g.,caudate,globus pallidus,and thalamus).The predictive accuracy of the established model was 81.1±8.0%in the training dataset.On the external validation dataset,the established model showed predictive accuracy of 78.5±2.1%.In the tests of identifying early and drug-naïve PD patients from healthy controls,the accuracies of the model constructed on the same 36 informative features were 80.3±7.1%and 79.1±6.5%,respectively,while the accuracies were 80.4±6.3%and 82.9±5.8%for diagnosing middle-to-late PD and those receiving drug management,respectively.The accuracies for predicting tremor-dominant and non-tremor-dominant PD were 79.8±6.9%and 79.1±6.5%,respectively.In conclusion,the multiple-tissue-specific brain radiomics model constructed from magnetic resonance imaging has the ability to discriminate PD and exhibits the advantages for improving PD diagnosis.展开更多
Missense mutations in the leucine rich repeat kinase 2 (LRRK2) gene are the leading genetic cause of autosomal dominant familial Parkinson’s disease. We previously reported that two mutations within the ROC domain, n...Missense mutations in the leucine rich repeat kinase 2 (LRRK2) gene are the leading genetic cause of autosomal dominant familial Parkinson’s disease. We previously reported that two mutations within the ROC domain, namely R1441C and A1442P, exhibit increased protein degradation leading to lowered steady state LRRK2 protein levels in HEK293 cells. More recently, the common WD40 domain LRRK2 haplotype, Met2397, which is a risk factor for Crohn’s disease, has been shown to lower steady state protein levels in HEK293 cells. In view of recent evidence implicating LRRK2 and inflamemation in PD, we investigated the effects of Met2397 on LRRK2 expression, and compared them to the Thr2397 variant and other LRRK2 mutants. In this study, we transfected HEK293 cells with plasmid constructs encoding the different LRRK2 variants, and analyzed the resulting protein levels by Western blot and flow cytometry. Here we found that both the Met2397 and Thr2397 haplotypes yield similar levels of LRRK2 protein expression and do not appear to impact cell viability in HEK293 cells, compared to other LRRK mutants. Thus, we have concluded that the Met2397 haplotype is unlikely to play a role in LRRK2 mediated or idiopathic PD.展开更多
The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesi...The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesis of neurodegenerative and psychiatric disorders, in particular Parkinson’s disease, which are associated with a subtle and chronic inflammatory response. A substantial body of evidence has demonstrated the non-neuronal expression of dopamine, its receptors and of the machinery that governs synthesis, secretion and storage of dopamine across several immune cell types. This review aims to summarize current knowledge on the role and expression of dopamine in immune cells. One of the goals is to decipher the complex mechanisms through which these cell types respond to dopamine, in order to address the impact this has on neurodegenerative and psychiatric pathologies such as Parkinson’s disease. A further aim is to illustrate the gaps in our understanding of the physiological roles of dopamine to encourage more targeted research focused on understanding the consequences of aberrant dopamine production on immune regulation. These highlights may prompt scientists in the field to consider alternative functions of this important neurotransmitter when targeting neuroinflammatory/neurodegenerative pathologies.展开更多
The expression of ectopic olfactory receptors （ORs） in melanized cells, such as the human brain nigrostri- atal dopaminergic neurons and skin melanocytes, is here pointed out. ORs are recognized to regulate skin mel...The expression of ectopic olfactory receptors （ORs） in melanized cells, such as the human brain nigrostri- atal dopaminergic neurons and skin melanocytes, is here pointed out. ORs are recognized to regulate skin melanogenesis, whereas OR expression in the dopaminergic neurons, characterized by accumulation of pigment neuromelanin, is downregulated in Parkinson＇s disease. Furthermore, the correlation between the pigmentation process and the dopamine pathway through ct-synuclein expression is also highlighted. Purposely, these ORs are suggested as therapeutic target for neurodegenerative diseases related to the pig- mentation disorders. Based on this evidence, a possible way of turning odorants into drugs, acting on three specific olfactory receptors, OR51E2, OR2AT4 and VN1R1, is thus introduced. Various odorous molecules are shown to interact with these ORs and their therapeutic potential against melanogenic and neurodegen- erative dysfunctions, including melanoma and Parkinson＇s disease, is suggested. Finally, a direct functional link between olfactory and endocrine systems in human brain through VNIR1 is proposed, helping to counteract female susceptibility to Parkinson＇s disease in quiescent life.展开更多
基金Supported by the National Natural Science Foundation of China, No. 30870846
文摘A recent multicenter study demonstrated that two variants of LRRK2, S1647T and R1398H, are associated with sporadic Parkinson＇s disease. The present study analyzed LRRK2 gene polymorphisms of S1647T and R1398H, demonstrating that the LRRK2 gene polymorphism S1647T variant is a risk factor for Parkinson＇s disease in a Chinese Han population. However, the R1398H variant did not influence the risk for Parkinson＇s disease. In addition, there was no difference in clinical symptoms of Parkinson＇s disease patients with various genotypes. Results showed that the LRRK2 S1647T variant was associated with an increased risk for developing early-onset Parkinson＇s disease in a Chinese Hart population. In addition, there was no correlation between LRRK2 S1647T, R1398H variants and G2385R, R1628P variants in Parkinson＇s disease patients.
基金This work was supported by the National Natural Science Foundation of China,Nos.81571225 and 81971192(both to AMX).
文摘Dysfunctional autophagy often occurs during the development of neurodegenerative diseases,such as Parkinson’s disease,Huntington’s disease,and Alzheimer’s disease.The purinergic P2X4 receptor is an ATP-gated ion channel that is widely expressed in the microglia,astrocytes,and neurons of the central and peripheral nervous systems.P2X4R is involved in the regulation of cellular excitability,synaptic transmission,and neuroinflammation.However,the role played by P2X4R in Parkinson’s disease remains poorly understood.Rat models of Parkinson’s disease were established by injecting 6-hydroxydopamine into the substantia nigra pars compacta.P2X4R-targeted small interfering RNA(siRNA)was injected into the same area 1 week before injury induction to inhibit the expression of the P2X4 receptor.The results showed that the inhibition of P2X4 receptor expression in Parkinson’s disease model rats reduced the rotation behavior induced by apomorphine treatment,increased the latency on the rotarod test,and upregulated the expression of tyrosine hydroxylase,brain-derived neurotrophic factor,LC3-II/LC3-I,Beclin-1,and phosphorylated tropomyosin receptor kinase B(TrkB)in brain tissue,while simultaneously reducing p62 levels.These findings suggest that P2X4 receptor activation might inhibit neuronal autophagy through the regulation of the brain-derived neurotrophic factor/TrkB signaling pathway,leading to dopaminergic neuron damage in the substantia nigra and the further inhibition of P2X4 receptor-mediated autophagy.These results indicate that P2X4 receptor might serve as a potential novel target for the treatment of Parkinson’s disease.This study was approved by the Animal Ethics Committee of Affiliated Hospital of Qingdao University(approval No.QYFYWZLL26119)on April 12,2016.
基金supported by the National Natural Science Foundation of China, Nos.82001767(to XJG), 81971577(to MMZ), 82171888(to XJX)the Natural Science Foundation of Zhejiang Province of China, Nos.LQ21H180008(to XJG), LQ20H180012(to MX)+1 种基金the China Postdoctoral Science Foundation, Nos.2021T140599(to XJG), 2019M662082(to XJG)the 13th Five-year Plan for National Key Research and Development Program of China, No.2016YFC1306600(to MMZ)
文摘Brain radiomics can reflect the characteristics of brain pathophysiology.However,the value of T1-weighted images,quantitative susceptibility mapping,and R2*mapping in the diagnosis of Parkinson’s disease(PD)was underestimated in previous studies.In this prospective study to establish a model for PD diagnosis based on brain imaging information,we collected high-resolution T1-weighted images,R2*mapping,and quantitative susceptibility imaging data from 171 patients with PD and 179 healthy controls recruited from August 2014 to August 2019.According to the inclusion time,123 PD patients and 121 healthy controls were assigned to train the diagnostic model,while the remaining 106 subjects were assigned to the external validation dataset.We extracted 1408 radiomics features,and then used data-driven feature selection to identify informative features that were significant for discriminating patients with PD from normal controls on the training dataset.The informative features so identified were then used to construct a diagnostic model for PD.The constructed model contained 36 informative radiomics features,mainly representing abnormal subcortical iron distribution(especially in the substantia nigra),structural disorganization(e.g.,in the inferior temporal,paracentral,precuneus,insula,and precentral gyri),and texture misalignment in the subcortical nuclei(e.g.,caudate,globus pallidus,and thalamus).The predictive accuracy of the established model was 81.1±8.0%in the training dataset.On the external validation dataset,the established model showed predictive accuracy of 78.5±2.1%.In the tests of identifying early and drug-naïve PD patients from healthy controls,the accuracies of the model constructed on the same 36 informative features were 80.3±7.1%and 79.1±6.5%,respectively,while the accuracies were 80.4±6.3%and 82.9±5.8%for diagnosing middle-to-late PD and those receiving drug management,respectively.The accuracies for predicting tremor-dominant and non-tremor-dominant PD were 79.8±6.9%and 79.1±6.5%,respectively.In conclusion,the multiple-tissue-specific brain radiomics model constructed from magnetic resonance imaging has the ability to discriminate PD and exhibits the advantages for improving PD diagnosis.
文摘Missense mutations in the leucine rich repeat kinase 2 (LRRK2) gene are the leading genetic cause of autosomal dominant familial Parkinson’s disease. We previously reported that two mutations within the ROC domain, namely R1441C and A1442P, exhibit increased protein degradation leading to lowered steady state LRRK2 protein levels in HEK293 cells. More recently, the common WD40 domain LRRK2 haplotype, Met2397, which is a risk factor for Crohn’s disease, has been shown to lower steady state protein levels in HEK293 cells. In view of recent evidence implicating LRRK2 and inflamemation in PD, we investigated the effects of Met2397 on LRRK2 expression, and compared them to the Thr2397 variant and other LRRK2 mutants. In this study, we transfected HEK293 cells with plasmid constructs encoding the different LRRK2 variants, and analyzed the resulting protein levels by Western blot and flow cytometry. Here we found that both the Met2397 and Thr2397 haplotypes yield similar levels of LRRK2 protein expression and do not appear to impact cell viability in HEK293 cells, compared to other LRRK mutants. Thus, we have concluded that the Met2397 haplotype is unlikely to play a role in LRRK2 mediated or idiopathic PD.
基金supported by a Research Development Fund(UTS Start-Up Grant 2018)from the University of Technology Sydney to AC。
文摘The dopaminergic system controls several vital central nervous system functions, including the control of movement, reward behaviors and cognition. Alterations of dopaminergic signaling are involved in the pathogenesis of neurodegenerative and psychiatric disorders, in particular Parkinson’s disease, which are associated with a subtle and chronic inflammatory response. A substantial body of evidence has demonstrated the non-neuronal expression of dopamine, its receptors and of the machinery that governs synthesis, secretion and storage of dopamine across several immune cell types. This review aims to summarize current knowledge on the role and expression of dopamine in immune cells. One of the goals is to decipher the complex mechanisms through which these cell types respond to dopamine, in order to address the impact this has on neurodegenerative and psychiatric pathologies such as Parkinson’s disease. A further aim is to illustrate the gaps in our understanding of the physiological roles of dopamine to encourage more targeted research focused on understanding the consequences of aberrant dopamine production on immune regulation. These highlights may prompt scientists in the field to consider alternative functions of this important neurotransmitter when targeting neuroinflammatory/neurodegenerative pathologies.
基金supported by the University of Ferrara(F72I15000470005)in the frame of the project FAR2014
文摘The expression of ectopic olfactory receptors （ORs） in melanized cells, such as the human brain nigrostri- atal dopaminergic neurons and skin melanocytes, is here pointed out. ORs are recognized to regulate skin melanogenesis, whereas OR expression in the dopaminergic neurons, characterized by accumulation of pigment neuromelanin, is downregulated in Parkinson＇s disease. Furthermore, the correlation between the pigmentation process and the dopamine pathway through ct-synuclein expression is also highlighted. Purposely, these ORs are suggested as therapeutic target for neurodegenerative diseases related to the pig- mentation disorders. Based on this evidence, a possible way of turning odorants into drugs, acting on three specific olfactory receptors, OR51E2, OR2AT4 and VN1R1, is thus introduced. Various odorous molecules are shown to interact with these ORs and their therapeutic potential against melanogenic and neurodegen- erative dysfunctions, including melanoma and Parkinson＇s disease, is suggested. Finally, a direct functional link between olfactory and endocrine systems in human brain through VNIR1 is proposed, helping to counteract female susceptibility to Parkinson＇s disease in quiescent life.
