A pathological feature of Parkinson’s disease(PD)is the progressive loss of dopaminergic neurons and decreased dopamine(DA)content in the substantia nigra pars compacta in PD brains.DA is the neurotransmitter of dopa...A pathological feature of Parkinson’s disease(PD)is the progressive loss of dopaminergic neurons and decreased dopamine(DA)content in the substantia nigra pars compacta in PD brains.DA is the neurotransmitter of dopaminergic neurons.Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology.Disturbances of DA synthesis,storage,transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models.DA is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products,including reactive oxygen species,DA quinones,and 3,4-dihydroxyphenylacetaldehyde.Here we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways,and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.展开更多
The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed patho...The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy.The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies.The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells.The benefits of induced pluripotent stem cell-based research are highlighted.Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared.The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated.Finally,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.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
基金supported by grants from the Singapore National Medical Research Council(CS-IRG,HLCA2022,STaR,OF LCG 000207)a clinical translational research programme in Parkinson’s disease and a Duke-Duke-NUS collaboration pilot grant.
文摘A pathological feature of Parkinson’s disease(PD)is the progressive loss of dopaminergic neurons and decreased dopamine(DA)content in the substantia nigra pars compacta in PD brains.DA is the neurotransmitter of dopaminergic neurons.Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology.Disturbances of DA synthesis,storage,transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models.DA is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products,including reactive oxygen species,DA quinones,and 3,4-dihydroxyphenylacetaldehyde.Here we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways,and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.
基金supported by Singapore National Medical Research Council(NMRC)grants,including CS-IRG,HLCA2022(to ZDZ),STaR,OF LCG 000207(to EKT)a Clinical Translational Research Programme in Parkinson's DiseaseDuke-Duke-NUS collaboration pilot grant(to ZDZ)。
文摘The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy.The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies.The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells.The benefits of induced pluripotent stem cell-based research are highlighted.Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared.The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated.Finally,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.
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.
