Parkinson's disease(PD)is a neurodegeneration disease withα-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with...Parkinson's disease(PD)is a neurodegeneration disease withα-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with PD.Exploring the pathology at an early stage contributes to the development of the disease-modifying strategy.Although the“gut–brain”hypothesis is proposed to explain the underlying mechanism,where the earlier lesioned site in the brain of gastricα-synuclein and howα-synuclein further spreads are not fully understood.Here we report that caudal raphe nuclei(CRN)are the early lesion site of gastricα-synuclein propagating through the spinal cord,while locus coeruleus(LC)and substantia nigra pars compacta(SNpc)were further affected over a time frame of 7 months.Pathologicalα-synuclein propagation via CRN leads to neuron loss and disordered neuron activity,accompanied by abnormal motor and non-motor behavior.Potential neuron circuits are observed among CRN,LC,and SNpc,which contribute to the venerability of dopaminergic neurons in SNpc.These results show that CRN is the key region for the gastricα-synuclein spread to the midbrain.Our study provides valuable details for the“gut–brain”hypothesis and proposes a valuable PD model for future research on early PD intervention.展开更多
基金This work was supported by the Natural Science Foundation of Beijing Municipality(No.7212156,China)CAMS Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1–026,China)National Natural Science Foundation of China,China(82373852).
文摘Parkinson's disease(PD)is a neurodegeneration disease withα-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with PD.Exploring the pathology at an early stage contributes to the development of the disease-modifying strategy.Although the“gut–brain”hypothesis is proposed to explain the underlying mechanism,where the earlier lesioned site in the brain of gastricα-synuclein and howα-synuclein further spreads are not fully understood.Here we report that caudal raphe nuclei(CRN)are the early lesion site of gastricα-synuclein propagating through the spinal cord,while locus coeruleus(LC)and substantia nigra pars compacta(SNpc)were further affected over a time frame of 7 months.Pathologicalα-synuclein propagation via CRN leads to neuron loss and disordered neuron activity,accompanied by abnormal motor and non-motor behavior.Potential neuron circuits are observed among CRN,LC,and SNpc,which contribute to the venerability of dopaminergic neurons in SNpc.These results show that CRN is the key region for the gastricα-synuclein spread to the midbrain.Our study provides valuable details for the“gut–brain”hypothesis and proposes a valuable PD model for future research on early PD intervention.
基金This work was supported by the National Basic Research Priorities Programme (G1999054000) National Nature Science Foundation of China (No.30000051+2 种基金 30100052 30200077 30300105) and Creative Foundation of Fourth Military Medical University (CX99F003)
