Parkinson's disease(PD), characterized by the loss of dopaminergic(DA) neurons in the substantia nigra pars compacta(SNpc) of the midbrain, is a prototype neurological disease that is suitable for cellular replace...Parkinson's disease(PD), characterized by the loss of dopaminergic(DA) neurons in the substantia nigra pars compacta(SNpc) of the midbrain, is a prototype neurological disease that is suitable for cellular replacement therapy. Levodopa has been utilized to replace the insufficient dopamine released by degenerating DA neurons since the 1960s and it remains the cornerstone of PD treatment. However, as the disease progresses.展开更多
In two recent articles published in Nature Neuroscience and Cell,Nelson et al.1 and Chen et al.2 have shown that a rare APOE3 Christchurch(APOE3Ch)variant,R136S,has protective effects on neurodegeneration in various A...In two recent articles published in Nature Neuroscience and Cell,Nelson et al.1 and Chen et al.2 have shown that a rare APOE3 Christchurch(APOE3Ch)variant,R136S,has protective effects on neurodegeneration in various Alzheimer’s disease(AD)model systems through attenuating tau pathology and regulating its related neuroimmune responses.Nelson et al.and Chen et al.have provided evidence that identifying the pathophysiologic clues and potential molecular targets from a protective variant such as APOE R136S,can be an attractive viable approach to develop AD therapeutics.展开更多
Restless legs syndrome(RLS)and Parkinson’s disease(PD)are both common neurological disorders.There has been much debate over whether an etiological link between these two diseases exists and whether they share a comm...Restless legs syndrome(RLS)and Parkinson’s disease(PD)are both common neurological disorders.There has been much debate over whether an etiological link between these two diseases exists and whether they share a common pathophysiology.Evidence pointing towards a link includes response to dopaminergic agents in PD and RLS,suggestive of underlying dopamine dysfunction in both conditions.The extrastriatal dopaminergic system,in particular altered spinal dopaminergic modulation,may be variably involved in PD patients with RLS symptoms.In addition,there is now evidence that the nigrostriatal system,primarily involved in PD,is also affected in RLS.Furthermore,an association of RLS with the parkin mutation has been suggested.The prevalence of RLS has also been reported to be increased in other disorders of dopamine regulation.However,clinical association studies and functional imaging have produced mixed findings.Conflicting accounts of emergence of RLS and improvement in RLS symptoms after deep brain stimulation(DBS)also contribute to the uncertainty surrounding the issue.Among the strongest arguments against a common pathophysiology is the role of iron in RLS and PD.While elevated iron levels in the substantia nigra contribute to oxidative stress in PD,RLS is a disorder of relative iron deficiency,with symptoms responding to replacement therapy.Recent ultrasonography studies have suggested that,despite overlapping clinical features,the mechanisms underlying idiopathic RLS and RLS associated with PD may differ.In this review,we provide a concise summary of the clinical,imaging and genetic evidence exploring the link between RLS and PD.展开更多
Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body fo...Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain areas.The detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear,and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in PD.However,the formation ofα-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD,possibly stemming from the consequence of protein misfolding and dysfunctional proteostasis.Proteostasis is the mechanism for maintaining protein homeostasis via modulation of protein translation,enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and autophagy.Deregulated protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes,leading to pathological protein aggregation and neurodegeneration in PD.In recent years,multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been identified.The potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.展开更多
Background:Aberrant aggregation ofα-synuclein(α-syn)is a key pathological feature of Parkinson’s disease(PD),but the precise role of intestinalα-syn in the progression of PD is unclear.In a number of genetic Droso...Background:Aberrant aggregation ofα-synuclein(α-syn)is a key pathological feature of Parkinson’s disease(PD),but the precise role of intestinalα-syn in the progression of PD is unclear.In a number of genetic Drosophila models of PD,α-syn was frequently ectopically expressed in the neural system to investigate the pathobiology.Method:We investigated the potential role of intestinalα-syn in PD pathogenesis using a Drosophila model.Humanα-syn was overexpressed in Drosophila guts,and life span,survival,immunofluorescence and climbing were evalu-ated.Immunofluorescence,Western blotting and reactive oxygen species(ROS)staining were performed to assess the effects of intestinalα-syn on intestinal dysplasia.High‐throughput RNA and 16S rRNA gene sequencing,quantitative RT‐PCR,immunofluorescence,and ROS staining were performed to determine the underlying molecular mechanism.Results:We found that the intestinalα-syn alone recapitulated many phenotypic and pathological features of PD,including impaired life span,loss of dopaminergic neurons,and progressive motor defects.The intestine-derivedα-syn disrupted intestinal homeostasis and accelerated the onset of intestinal ageing.Moreover,intestinal expression ofα-syn induced dysbiosis,while microbiome depletion was efficient to restore intestinal homeostasis and ameliorate the progression of PD.Intestinalα-syn triggered ROS,and eventually led to the activation of the dual oxidase(DUOX)-ROS-Jun N-terminal Kinase(JNK)pathway.In addition,α-syn from both the gut and the brain synergized to accelerate the progression of PD.Conclusions:The intestinal expression ofα-syn recapitulates many phenotypic and pathologic features of PD,and induces dysbiosis that aggravates the pathology through the DUOX-ROS-JNK pathway in Drosophila.Our findings provide new insights into the role of intestinalα-syn in PD pathophysiology.展开更多
基金the Singapore Ministry of Health's National Medical Research Council (Open Fund Large Collaborative Grant (MOH-000207)Singapore Translational Research (STaR) Investigator A word (NMRC/STaR/0030/2018) to EKT,CS-IRG-NIG,OF-YIRG and TA award to BX) for their support。
文摘Parkinson's disease(PD), characterized by the loss of dopaminergic(DA) neurons in the substantia nigra pars compacta(SNpc) of the midbrain, is a prototype neurological disease that is suitable for cellular replacement therapy. Levodopa has been utilized to replace the insufficient dopamine released by degenerating DA neurons since the 1960s and it remains the cornerstone of PD treatment. However, as the disease progresses.
基金Singapore Ministry of Health’s National Medical Research Council for their support(Open Fund Large Collaborative Grant(MOH-000207)Singapore Translational Research(STaR)Investigator Award(NMRC/STaR/0030/2018)to E.-K.T.,TA award and OF-YIRG to B.X.)。
文摘In two recent articles published in Nature Neuroscience and Cell,Nelson et al.1 and Chen et al.2 have shown that a rare APOE3 Christchurch(APOE3Ch)variant,R136S,has protective effects on neurodegeneration in various Alzheimer’s disease(AD)model systems through attenuating tau pathology and regulating its related neuroimmune responses.Nelson et al.and Chen et al.have provided evidence that identifying the pathophysiologic clues and potential molecular targets from a protective variant such as APOE R136S,can be an attractive viable approach to develop AD therapeutics.
文摘Restless legs syndrome(RLS)and Parkinson’s disease(PD)are both common neurological disorders.There has been much debate over whether an etiological link between these two diseases exists and whether they share a common pathophysiology.Evidence pointing towards a link includes response to dopaminergic agents in PD and RLS,suggestive of underlying dopamine dysfunction in both conditions.The extrastriatal dopaminergic system,in particular altered spinal dopaminergic modulation,may be variably involved in PD patients with RLS symptoms.In addition,there is now evidence that the nigrostriatal system,primarily involved in PD,is also affected in RLS.Furthermore,an association of RLS with the parkin mutation has been suggested.The prevalence of RLS has also been reported to be increased in other disorders of dopamine regulation.However,clinical association studies and functional imaging have produced mixed findings.Conflicting accounts of emergence of RLS and improvement in RLS symptoms after deep brain stimulation(DBS)also contribute to the uncertainty surrounding the issue.Among the strongest arguments against a common pathophysiology is the role of iron in RLS and PD.While elevated iron levels in the substantia nigra contribute to oxidative stress in PD,RLS is a disorder of relative iron deficiency,with symptoms responding to replacement therapy.Recent ultrasonography studies have suggested that,despite overlapping clinical features,the mechanisms underlying idiopathic RLS and RLS associated with PD may differ.In this review,we provide a concise summary of the clinical,imaging and genetic evidence exploring the link between RLS and PD.
基金The Singapore National Medical Research Council(NMRC)grants including STaR and a clinical translational research program in Parkinson’s disease.
文摘Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain areas.The detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear,and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in PD.However,the formation ofα-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD,possibly stemming from the consequence of protein misfolding and dysfunctional proteostasis.Proteostasis is the mechanism for maintaining protein homeostasis via modulation of protein translation,enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and autophagy.Deregulated protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes,leading to pathological protein aggregation and neurodegeneration in PD.In recent years,multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been identified.The potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.
基金the Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research(STaR)Investigator Award(NMRC/STaR/0030/2018)National Parkinson’s Disease Translational Clinical Research Programme(013-NNI/2014)+1 种基金National Medical Research Council Singapore,OF LCG 000207,SPARKS II,and Innovative Research Group Project of the the National Natural Science Foundation of China(31501175)Talents in Anhui Agricultural University(RC342201).
文摘Background:Aberrant aggregation ofα-synuclein(α-syn)is a key pathological feature of Parkinson’s disease(PD),but the precise role of intestinalα-syn in the progression of PD is unclear.In a number of genetic Drosophila models of PD,α-syn was frequently ectopically expressed in the neural system to investigate the pathobiology.Method:We investigated the potential role of intestinalα-syn in PD pathogenesis using a Drosophila model.Humanα-syn was overexpressed in Drosophila guts,and life span,survival,immunofluorescence and climbing were evalu-ated.Immunofluorescence,Western blotting and reactive oxygen species(ROS)staining were performed to assess the effects of intestinalα-syn on intestinal dysplasia.High‐throughput RNA and 16S rRNA gene sequencing,quantitative RT‐PCR,immunofluorescence,and ROS staining were performed to determine the underlying molecular mechanism.Results:We found that the intestinalα-syn alone recapitulated many phenotypic and pathological features of PD,including impaired life span,loss of dopaminergic neurons,and progressive motor defects.The intestine-derivedα-syn disrupted intestinal homeostasis and accelerated the onset of intestinal ageing.Moreover,intestinal expression ofα-syn induced dysbiosis,while microbiome depletion was efficient to restore intestinal homeostasis and ameliorate the progression of PD.Intestinalα-syn triggered ROS,and eventually led to the activation of the dual oxidase(DUOX)-ROS-Jun N-terminal Kinase(JNK)pathway.In addition,α-syn from both the gut and the brain synergized to accelerate the progression of PD.Conclusions:The intestinal expression ofα-syn recapitulates many phenotypic and pathologic features of PD,and induces dysbiosis that aggravates the pathology through the DUOX-ROS-JNK pathway in Drosophila.Our findings provide new insights into the role of intestinalα-syn in PD pathophysiology.
