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
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
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.
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.
