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
In addition to the cardinal motor symptoms,pain is a major non-motor symptom of Parkinson's disease(PD).Neuroinflammation in the substantia nigra pars compacta and dorsal striatum is involved in neurodegeneration ...In addition to the cardinal motor symptoms,pain is a major non-motor symptom of Parkinson's disease(PD).Neuroinflammation in the substantia nigra pars compacta and dorsal striatum is involved in neurodegeneration in PD.But the polarization of microglia and astrocytes in the dorsal striatum and their contribution to motor deficits and hyperalgesia in PD have not been characterized.In the present study,we observed that hemiparkinsonian mice established by unilateral 6-OHDA injection in the medial forebrain bundle exhibited motor deficits and mechanical allodynia.In these mice,both microglia and astrocytes in the dorsal striatum were activated and polarized to M1/M2 microglia and A1/A2 astrocytes as genes specific to these cells were upregulated.These effects peaked 7 days after 6-OHDA injection.Meanwhile,striatal astrocytes in parkinsonian mice also displayed hyperpolarized membrane potentials,enhanced voltage-gated potassium currents,and dysfunction in inwardly rectifying potassium channels and glutamate transporters.Systemic administration of minocycline,a microglia inhibitor,attenuated the expression of genes specific to M1 microglia and A1 astrocytes in the dorsal striatum(but not those specific to M2 microglia and A2 astrocytes),attenuated the damage in the nigrostriatal dopaminergic system,and alleviated the motor deficits and mechanical allodynia in parkinsonian mice.By contrast,local administration of minocycline into the dorsal striatum of parkinsonian mice mitigated only hyperalgesia.This study suggests that M1 microglia and A1 astrocytes in the dorsal striatum may play important roles in the development of pathophysiology underlying hyperalgesia in the early stages of PD.展开更多
A preferential dysfunction/loss of dopaminergic(DA)neurons in the substantia nigra pars compacta(SNpc)accounts for the main motor symptoms of Parkinson’s disease(PD),the most common degenerative movement disorder.How...A preferential dysfunction/loss of dopaminergic(DA)neurons in the substantia nigra pars compacta(SNpc)accounts for the main motor symptoms of Parkinson’s disease(PD),the most common degenerative movement disorder.However,the neuronal loss is not stochastic,but rather displays regionally selectivity,indicating the existence of different DA subpopulations in the SNpc.To identify the underlying molecular determinants is thereby instrumental in understanding the pathophysiological mechanisms of PD-related neuron dysfunction/loss and offering new therapeutic targets.Recently,we have demonstrated that aldehyde dehydrogenase 1(ALDH1A1)is one such molecular determinant that defines and protects an SNpc DA neuron subpopulation preferentially affected in PD.In this review,we provide further analysis and discussion on the roles of ALDH1A1 in the function and survival of SNpc DA neurons in both rodent and human brains.We also explore the feasibility of ALDH1A1 as a potential biomarker and therapeutic target for PD.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the National Natural Science Foundation of China(81971038,82071231,82171235,82271293,81870891)the Fund for Jiangsu Province Specially-Appointed Professor(C.X.,C.Z.)+1 种基金the Natural Science Foundation of Jiangsu Province(BK20211349)the Leadership Program in Xuzhou Medical University(JBGS202203).
文摘In addition to the cardinal motor symptoms,pain is a major non-motor symptom of Parkinson's disease(PD).Neuroinflammation in the substantia nigra pars compacta and dorsal striatum is involved in neurodegeneration in PD.But the polarization of microglia and astrocytes in the dorsal striatum and their contribution to motor deficits and hyperalgesia in PD have not been characterized.In the present study,we observed that hemiparkinsonian mice established by unilateral 6-OHDA injection in the medial forebrain bundle exhibited motor deficits and mechanical allodynia.In these mice,both microglia and astrocytes in the dorsal striatum were activated and polarized to M1/M2 microglia and A1/A2 astrocytes as genes specific to these cells were upregulated.These effects peaked 7 days after 6-OHDA injection.Meanwhile,striatal astrocytes in parkinsonian mice also displayed hyperpolarized membrane potentials,enhanced voltage-gated potassium currents,and dysfunction in inwardly rectifying potassium channels and glutamate transporters.Systemic administration of minocycline,a microglia inhibitor,attenuated the expression of genes specific to M1 microglia and A1 astrocytes in the dorsal striatum(but not those specific to M2 microglia and A2 astrocytes),attenuated the damage in the nigrostriatal dopaminergic system,and alleviated the motor deficits and mechanical allodynia in parkinsonian mice.By contrast,local administration of minocycline into the dorsal striatum of parkinsonian mice mitigated only hyperalgesia.This study suggests that M1 microglia and A1 astrocytes in the dorsal striatum may play important roles in the development of pathophysiology underlying hyperalgesia in the early stages of PD.
基金by the Intramural Research Program of National Institute on Aging,National Institutes of Health(AG000959-07 and AG000945-03).
文摘A preferential dysfunction/loss of dopaminergic(DA)neurons in the substantia nigra pars compacta(SNpc)accounts for the main motor symptoms of Parkinson’s disease(PD),the most common degenerative movement disorder.However,the neuronal loss is not stochastic,but rather displays regionally selectivity,indicating the existence of different DA subpopulations in the SNpc.To identify the underlying molecular determinants is thereby instrumental in understanding the pathophysiological mechanisms of PD-related neuron dysfunction/loss and offering new therapeutic targets.Recently,we have demonstrated that aldehyde dehydrogenase 1(ALDH1A1)is one such molecular determinant that defines and protects an SNpc DA neuron subpopulation preferentially affected in PD.In this review,we provide further analysis and discussion on the roles of ALDH1A1 in the function and survival of SNpc DA neurons in both rodent and human brains.We also explore the feasibility of ALDH1A1 as a potential biomarker and therapeutic target for PD.
