Parkinson’s disease(PD)is a common neurodegenerative disease,characterized clinically by both motor and non-motor symptoms.Pathologically,PD is hallmarked by the loss of dopaminergic neurons in the substantia nigra(S...Parkinson’s disease(PD)is a common neurodegenerative disease,characterized clinically by both motor and non-motor symptoms.Pathologically,PD is hallmarked by the loss of dopaminergic neurons in the substantia nigra(SN)and the formation ofα-synuclein(α-syn)containing inclusion bodies(Lewy pathology)in the surviving neurons.Diagnosis of PD is still based on clinical features.However,owing to the complexity,heterogeneity,and overlapping of its symptoms with other Parkinsonian disorders,correct diagnosis of PD remains a challenge,especially in the early stages.Therefore,there is an urgent need for biomarkers that can help correctly diagnose PD,differentiate PD from other Parkinsonian disorders,monitor the progression of the disease,and evaluate the therapeutic efficacy.Various molecules have been investigated for their utility in diagnosing PD,among whichα-syn is the most extensively investigated one due to its close implication in the etiology and pathogenesis of PD and related diseases.During the past decade,various species ofα-syn,including total,oligomeric,and phosphorylatedα-syn in various tissues,have been investigated for their utility as a potential biomarker for PD diagnosis and differential diagnosis.Various forms ofα-syn in body fluids,including cerebrospinal fluid(CSF),blood plasma,and saliva,are among the ones that are extensively investigated,since the body fluids are relatively accessible compared to the peripheral tissues.The aim of this review is to summarize the progress of studies on the utility ofα-syn in body fluid as a biomarker for PD diagnosis and differential diagnosis.展开更多
Alpha-synucleinopathies(α-synucleinopathies)are a diverse group of neurodegenerative diseases comprising Parkinson’s disease(PD),dementia with Lewy bodies(DLB),and multiple system atrophy(MSA).Although in all these ...Alpha-synucleinopathies(α-synucleinopathies)are a diverse group of neurodegenerative diseases comprising Parkinson’s disease(PD),dementia with Lewy bodies(DLB),and multiple system atrophy(MSA).Although in all these diseases there exist abnormal accumulation of alpha-synuclein(α-syn)aggregates in nerve tissues,the pathological lesions formed byα-syn aggregates and their cellular locations are quite different.In PD and DLB,the hallmark pathological lesions are Lewy bodies(LBs)and Lewy neurites(LNs),which are localized in the neuronal somata and processes.In MSA,the characteristic pathologic structures are glial cytoplasmic inclusions,which are deposited in the cytoplasm of oligodendrocytes.The fact that PD and MSA have distinct pathologicalα-syn lesions suggest that different mechanisms play a role in the pathogenesis of the two diseases.In this review article,we compare the clinical manifestations and pathological features of PD and MSA,the two common synucleinopathies,and discuss the potential mechanisms for the formation ofα-syn aggregates and their pathologic roles in PD and MSA.展开更多
Univocal identification of retinal ganglion cells(RGCs) is an essential prerequisite for studying their degeneration and neuroprotection. Before the advent of phenotypic markers, RGCs were normally identified using re...Univocal identification of retinal ganglion cells(RGCs) is an essential prerequisite for studying their degeneration and neuroprotection. Before the advent of phenotypic markers, RGCs were normally identified using retrograde tracing of retinorecipient areas. This is an invasive technique, and its use is precluded in higher mammals such as monkeys. In the past decade, several RGC markers have been described. Here, we reviewed and analyzed the specificity of nine markers used to identify all or most RGCs, i.e., pan-RGC markers, in rats, mice, and macaques. The best markers in the three species in terms of specificity, proportion of RGCs labeled, and indicators of viability were BRN3A, expressed by vision-forming RGCs, and RBPMS, expressed by vision-and non-vision-forming RGCs. NEUN, often used to identify RGCs, was expressed by non-RGCs in the ganglion cell layer, and therefore was not RGC-specific. γ-SYN, TUJ1, and NF-L labeled the RGC axons, which impaired the detection of their somas in the central retina but would be good for studying RGC morphology. In rats, TUJ1 and NF-L were also expressed by non-RGCs. BM88, ERRβ,and PGP9.5 are rarely used as markers, but they identified most RGCs in the rats and macaques and ERRβ in mice. However, PGP9.5 was also expressed by non-RGCs in rats and macaques and BM88 and ERRβ were not suitable markers of viability.展开更多
Parkinson’s disease (PD) is the second most common neurodegenerative disease. Its most prominent pathological features are the loss of dopaminergic neurons in the substantia nigra pars compacta and the deposition of ...Parkinson’s disease (PD) is the second most common neurodegenerative disease. Its most prominent pathological features are the loss of dopaminergic neurons in the substantia nigra pars compacta and the deposition of intraneuronal inclusions named Lewy bodies. Currently, the pathophysiological mechanisms of PD are not fully understood. Growing evidence suggests that insulin resistance, diabetes and PD share similar pathological processes. This raises the possibility that defective insulin signaling pathways contribute to the occurrence and development of PD. In this article, we firstly reviewed the evidence of insulin resistance from epidemiology, PD patients and animal models. We also explained the insulin signal pathways in central nervous system. We then showed the evidence that insulin resistance participates in the pathogenesis of PD via protein aggregation, mitochondrial dysfunction, neural inflammation and cognitive impairment. Finally, we introduced four categories of drugs that facilitate insulin signaling and their effects on neurodegeneration in PD.展开更多
Parkinson’s disease(PD)is a common age-related neurodegenerative disease characterized by movement disorders.The hallmark pathological lesions of PD are the formation of Lewy pathology in selected populations of neur...Parkinson’s disease(PD)is a common age-related neurodegenerative disease characterized by movement disorders.The hallmark pathological lesions of PD are the formation of Lewy pathology in selected populations of neurons throughout the nervous system.Braak and his colleagues created a staging system for PD describing the connection between Lewy pathology and disease severity.They proposed that Lewy pathology might be initially triggered by exogenous pathogens targeting the enteric or olfactory nervous system,then spread in a prion-like propagation manner from the peripheral nerves to the lower brainstem and midbrain,before finally reaching higher cortical structures,causing a sequential occurrence of the non-motor and motor symptoms,depending on the lesioned neurons.However,emerging evidence also supports a functional threshold hypothesis proposed by Engelender and Isacson in which Lewy pathology may occur parallelly in the central and peripheral nervous systems and the symptoms only begin when the functional reserve of the affected neurons(and their connecting brain regions)is unable to allow for network compensation.Consequently,early symptoms of PD reflect the loss of function in the least compensated systems,such as the enteric and olfactory nervous systems,rather than the spread of Lewy pathology from the peripheral to the central nervous systems.The current review article provides a comprehensive overview of the evidence supporting a merged mechanism that the neurodegeneration in PD happens to those neurons that are not only intrinsically vulnerable but also affected by the spread of Lewy pathology.展开更多
Background:Parkinson’s disease(PD)is one of the most common neurodegenerative diseases,neuropathologically characterized by misfolded protein aggregation,called Lewy bodies and Lewy neurites.PD is a slow-progressive ...Background:Parkinson’s disease(PD)is one of the most common neurodegenerative diseases,neuropathologically characterized by misfolded protein aggregation,called Lewy bodies and Lewy neurites.PD is a slow-progressive disease with colonic dysfunction appearing in the prodromal stage and lasting throughout the course of the disease.Methods:In order to study PD pathology in the colon,we examined the age-dependent morphological and pathological changes in the colon of a PD mouse model expressing human wildtype α-synuclein(α-syn)fused with the green fluorescent protein(GFP),under the endogenous mouse α-syn promoter.Results:We observed an age-dependent progressive expression and accumulation of α-syn-GFP in the enteric neurons of Meissner’s(submucosal)and Auerbach’s(myenteric)plexuses of the colon.Additionally,the phosphorylation of α-syn at serine 129 also increased with age and the aggregation ofα-syn-GFP coincided with the appearance of motor deficits at 9 months of age.Furthermore,α-syn(-GFP)distinctly co-localized with different subtypes of neurons,as identified by immunohistochemical labeling of vasoactive intestinal peptide(VIP),neuronal nitric oxide synthase(nNOS),and calretinin.Conclusions:Our results show the development of α-syn pathology in the enteric neurons of the colon in a PD mouse model,which coincide with the appearance of motor deficits.Our mouse model possesses the potential and uniqueness for studying PD gastrointestinal dysfunction.展开更多
文摘Parkinson’s disease(PD)is a common neurodegenerative disease,characterized clinically by both motor and non-motor symptoms.Pathologically,PD is hallmarked by the loss of dopaminergic neurons in the substantia nigra(SN)and the formation ofα-synuclein(α-syn)containing inclusion bodies(Lewy pathology)in the surviving neurons.Diagnosis of PD is still based on clinical features.However,owing to the complexity,heterogeneity,and overlapping of its symptoms with other Parkinsonian disorders,correct diagnosis of PD remains a challenge,especially in the early stages.Therefore,there is an urgent need for biomarkers that can help correctly diagnose PD,differentiate PD from other Parkinsonian disorders,monitor the progression of the disease,and evaluate the therapeutic efficacy.Various molecules have been investigated for their utility in diagnosing PD,among whichα-syn is the most extensively investigated one due to its close implication in the etiology and pathogenesis of PD and related diseases.During the past decade,various species ofα-syn,including total,oligomeric,and phosphorylatedα-syn in various tissues,have been investigated for their utility as a potential biomarker for PD diagnosis and differential diagnosis.Various forms ofα-syn in body fluids,including cerebrospinal fluid(CSF),blood plasma,and saliva,are among the ones that are extensively investigated,since the body fluids are relatively accessible compared to the peripheral tissues.The aim of this review is to summarize the progress of studies on the utility ofα-syn in body fluid as a biomarker for PD diagnosis and differential diagnosis.
基金the authors are supported by grants from Natural Science Foundation of China(81671244,81371200,and 81401042)a special fund from Key Laboratory of Neurodegenerative Disease,Ministry of Education(PXM2019_026283_000002)+1 种基金Beijing Municipal Science and Technology Commission(Z161100005116011,Z171100000117013)Beijing Municipal commission of Health and Family Planning(PXM2017_026283_000002).
文摘Alpha-synucleinopathies(α-synucleinopathies)are a diverse group of neurodegenerative diseases comprising Parkinson’s disease(PD),dementia with Lewy bodies(DLB),and multiple system atrophy(MSA).Although in all these diseases there exist abnormal accumulation of alpha-synuclein(α-syn)aggregates in nerve tissues,the pathological lesions formed byα-syn aggregates and their cellular locations are quite different.In PD and DLB,the hallmark pathological lesions are Lewy bodies(LBs)and Lewy neurites(LNs),which are localized in the neuronal somata and processes.In MSA,the characteristic pathologic structures are glial cytoplasmic inclusions,which are deposited in the cytoplasm of oligodendrocytes.The fact that PD and MSA have distinct pathologicalα-syn lesions suggest that different mechanisms play a role in the pathogenesis of the two diseases.In this review article,we compare the clinical manifestations and pathological features of PD and MSA,the two common synucleinopathies,and discuss the potential mechanisms for the formation ofα-syn aggregates and their pathologic roles in PD and MSA.
基金supported by the Spanish Ministry of Economy and Competitiveness(PID2019-106498GB-I0)Instituto de Salud Carlos III,Fondo Europeo de Desarrollo Regional“Una manera de hacer Europa”(PI19/00071)+2 种基金Fundación Séneca,Agencia de Ciencia y Tecnología Región de Murcia(19881/GERM/15)Spanish Ministry of Science and Innovation(PID 2019-106498 GB-I00)Intramural Research Program of the National Eye Institute,National Institutes of Health(NIH/NEI RO1 EY029087)。
文摘Univocal identification of retinal ganglion cells(RGCs) is an essential prerequisite for studying their degeneration and neuroprotection. Before the advent of phenotypic markers, RGCs were normally identified using retrograde tracing of retinorecipient areas. This is an invasive technique, and its use is precluded in higher mammals such as monkeys. In the past decade, several RGC markers have been described. Here, we reviewed and analyzed the specificity of nine markers used to identify all or most RGCs, i.e., pan-RGC markers, in rats, mice, and macaques. The best markers in the three species in terms of specificity, proportion of RGCs labeled, and indicators of viability were BRN3A, expressed by vision-forming RGCs, and RBPMS, expressed by vision-and non-vision-forming RGCs. NEUN, often used to identify RGCs, was expressed by non-RGCs in the ganglion cell layer, and therefore was not RGC-specific. γ-SYN, TUJ1, and NF-L labeled the RGC axons, which impaired the detection of their somas in the central retina but would be good for studying RGC morphology. In rats, TUJ1 and NF-L were also expressed by non-RGCs. BM88, ERRβ,and PGP9.5 are rarely used as markers, but they identified most RGCs in the rats and macaques and ERRβ in mice. However, PGP9.5 was also expressed by non-RGCs in rats and macaques and BM88 and ERRβ were not suitable markers of viability.
基金grants of the National Key R&D Program of China (2016YFC1306000)National Natural Science Foundation of China (81870994).
文摘Parkinson’s disease (PD) is the second most common neurodegenerative disease. Its most prominent pathological features are the loss of dopaminergic neurons in the substantia nigra pars compacta and the deposition of intraneuronal inclusions named Lewy bodies. Currently, the pathophysiological mechanisms of PD are not fully understood. Growing evidence suggests that insulin resistance, diabetes and PD share similar pathological processes. This raises the possibility that defective insulin signaling pathways contribute to the occurrence and development of PD. In this article, we firstly reviewed the evidence of insulin resistance from epidemiology, PD patients and animal models. We also explained the insulin signal pathways in central nervous system. We then showed the evidence that insulin resistance participates in the pathogenesis of PD via protein aggregation, mitochondrial dysfunction, neural inflammation and cognitive impairment. Finally, we introduced four categories of drugs that facilitate insulin signaling and their effects on neurodegeneration in PD.
基金the authors were supported by grants from Natural Science Foundation of China(81671244,81371200,and 81401042)Beijing Municipal Science and Technology Commission(Z161100005116011,Z171100000117013)+1 种基金Beijing Municipal Commission of Health and Family Planning(PXM2017_026283_000002)Beijing Nova Program(Z181100006218052,xx2018096)to Yang WW.
文摘Parkinson’s disease(PD)is a common age-related neurodegenerative disease characterized by movement disorders.The hallmark pathological lesions of PD are the formation of Lewy pathology in selected populations of neurons throughout the nervous system.Braak and his colleagues created a staging system for PD describing the connection between Lewy pathology and disease severity.They proposed that Lewy pathology might be initially triggered by exogenous pathogens targeting the enteric or olfactory nervous system,then spread in a prion-like propagation manner from the peripheral nerves to the lower brainstem and midbrain,before finally reaching higher cortical structures,causing a sequential occurrence of the non-motor and motor symptoms,depending on the lesioned neurons.However,emerging evidence also supports a functional threshold hypothesis proposed by Engelender and Isacson in which Lewy pathology may occur parallelly in the central and peripheral nervous systems and the symptoms only begin when the functional reserve of the affected neurons(and their connecting brain regions)is unable to allow for network compensation.Consequently,early symptoms of PD reflect the loss of function in the least compensated systems,such as the enteric and olfactory nervous systems,rather than the spread of Lewy pathology from the peripheral to the central nervous systems.The current review article provides a comprehensive overview of the evidence supporting a merged mechanism that the neurodegeneration in PD happens to those neurons that are not only intrinsically vulnerable but also affected by the spread of Lewy pathology.
基金This work was supported by the National Natural Science Foundation(81430025)also to the supports of the Swedish Research Council(K2015-61X-22297-03-4),EU-JPND(aSynProtec)and EU-JPND(REfreAME),EU H2020-MSCA-ITN-2016(Syndegen),BAGADILICO-Excellence in Parkinson and Huntington Research,the Strong Research Environment MultiPark(Multidisciplinary research on Parkinson’s disease)+1 种基金the Swedish Parkinson Foundation(Parkinsonfonden),Torsten Söderbergs Foundation,Olle Engkvist Byggmästere FoundationW.L.is supported by a scholarship from the China Scholarship Council.
文摘Background:Parkinson’s disease(PD)is one of the most common neurodegenerative diseases,neuropathologically characterized by misfolded protein aggregation,called Lewy bodies and Lewy neurites.PD is a slow-progressive disease with colonic dysfunction appearing in the prodromal stage and lasting throughout the course of the disease.Methods:In order to study PD pathology in the colon,we examined the age-dependent morphological and pathological changes in the colon of a PD mouse model expressing human wildtype α-synuclein(α-syn)fused with the green fluorescent protein(GFP),under the endogenous mouse α-syn promoter.Results:We observed an age-dependent progressive expression and accumulation of α-syn-GFP in the enteric neurons of Meissner’s(submucosal)and Auerbach’s(myenteric)plexuses of the colon.Additionally,the phosphorylation of α-syn at serine 129 also increased with age and the aggregation ofα-syn-GFP coincided with the appearance of motor deficits at 9 months of age.Furthermore,α-syn(-GFP)distinctly co-localized with different subtypes of neurons,as identified by immunohistochemical labeling of vasoactive intestinal peptide(VIP),neuronal nitric oxide synthase(nNOS),and calretinin.Conclusions:Our results show the development of α-syn pathology in the enteric neurons of the colon in a PD mouse model,which coincide with the appearance of motor deficits.Our mouse model possesses the potential and uniqueness for studying PD gastrointestinal dysfunction.
