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1.
J Vis Exp ; (167)2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33522500

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. Gait abnormalities, including decreased arm swing, slower walking speed, and shorter steps are common in PD patients and appear early in the course of disease. Thus, the quantification of motor patterns in animal models of PD will be important for phenotypic characterization during disease course and upon therapeutic treatment. Most cases of PD are idiopathic; however, the identification of hereditary forms of PD uncovered gene mutations and variants, such as loss-of-function mutations in Pink1 and Parkin, two proteins involved in mitochondrial quality control that could be harnessed to create animal models. While mice are resistant to neurodegeneration upon loss of Pink1 and Parkin (single and combined deletion), in rats, Pink1 but not Parkin deficiency leads to nigral DA neuron loss and motor impairment. Here, we report the utility of FTIR imaging to uncover gait changes in freely walking young (2 months of age) male rats with combined loss of Pink1 and Parkin prior to the development of gross visually apparent motor abnormality as these rats age (observed at 4-6 months), characterized by hindlimb dragging as previously reported in Pink1 knockout (KO) rats.


Assuntos
Análise da Marcha , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Marcha , Técnicas de Inativação de Genes , Humanos , Masculino , Camundongos , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Substância Negra/patologia , Ubiquitina-Proteína Ligases/metabolismo , Gravação em Vídeo
2.
Neurosci Lett ; 740: 135425, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33075422

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Oxidative stress has been identified as one of the major causes of nigrostriatal degeneration in PD. Ascorbic acid plays a role as an efficient antioxidant to protect cells from free radical damage, but it is easily oxidized and loses its antioxidant activity. To overcome this limitation, we have recently developed NXP031, a single-stranded DNA aptamer that binds to ascorbic acid with excellent specificity, reducing its oxidation and increasing its efficacy. This study investigated the neuroprotective effects of NXP031 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model. Acute degeneration of nigral dopaminergic neurons was induced by four consecutive treatments of MPTP (20 mg/kg) in male C57BL/6 J mice. NXP031 (Vitamin C/Aptamin C 200 mg/4 mg/kg) was administered intraperitoneally for 5 days following MPTP. We observed that the administration of NXP031 ameliorated MPTP-induced loss of dopaminergic neurons in the SN and exhibited improvement of MPTP-mediated motor impairment. We further found that NXP031 increased plasma ascorbic acid levels and inhibited microglia activation-induced neuroinflammation in the SN, which might contribute to the protective effects of NXP031 on nigrostriatal degeneration. Our findings suggest that NXP031 could be a potential therapeutic intervention in PD.


Assuntos
Intoxicação por MPTP/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Animais , Ácido Ascórbico/sangue , Ácido Ascórbico/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia , Degeneração Neural/patologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Equilíbrio Postural/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Substância Negra/patologia
3.
Clin Nucl Med ; 46(2): 119-124, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33323728

RESUMO

INTRODUCTION: Degeneration of dopaminergic, nigrostriatal neurons is the hallmark of Parkinson disease (PD), and PET quantification of dopamine transporters is a widely accepted method for differential diagnosis between idiopathic PD and essential tremor. [18F]PR04.MZ is a new PET tracer with excellent imaging properties allowing for precise quantification of striatal and extrastriatal dopamine transporter. Here we describe our initial experience with [18F]PR04.MZ PET/CT in a larger cohort of healthy controls and PD patients as a proof-of-concept study for this tracer. METHODS: Eighteen healthy subjects, 19 early PD patients (Hoehn-Yahr I-II), and 13 moderate-advanced PD patients (Hoehn-Yahr III-IV) underwent static PET/CT scans 60 to 90 minutes after injection of 5.16 ± 1.03 mCi (191 ± 38 MBq) [18F]PR04.MZ. Specific binding ratios (SBRs) were calculated for caudate nucleus, anterior putamen, posterior putamen, substantia nigra (SNpc), compared between different groups and correlated with clinical ratings. RESULTS: [18F]PR04.MZ showed very high and specific uptake in the putamen, caudate, and substantia nigra pars compacta and very low nonspecific binding in other brain regions, and SBR values for the control group were 22.3 ± 4.1, 19.1 ± 3.5, and 5.4 ± 1.2, respectively. A reduction of SBR values was observed in all regions and in both initial and moderate PD, ranging from 35% to 89% (P < 0.001). The observed pattern of reduction was posterior putamen > anterior putamen > substantia nigra pars compacta > caudate, with contralateral posterior putamen being the most affected region. Rostrocaudal depletion gradient was evident in all PD patients and progression correlated with motor manifestations. CONCLUSIONS: [18F]PR04.MZ PET/CT is a highly sensitive imaging modality for the detection of dopaminergic deficit in nigrostriatal pathways in PD.


Assuntos
Neurônios/patologia , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Substância Negra/patologia , Idoso , Estudos de Coortes , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Doença de Parkinson/metabolismo
4.
Nat Commun ; 11(1): 4183, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826893

RESUMO

We describe a human single-nuclei transcriptomic atlas for the substantia nigra (SN), generated by sequencing approximately 17,000 nuclei from matched cortical and SN samples. We show that the common genetic risk for Parkinson's disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression, including mitochondrial functioning, protein folding and ubiquitination pathways. We identify a distinct cell type association between PD risk and oligodendrocyte-specific gene expression. Unlike Alzheimer's disease (AD), we find no association between PD risk and microglia or astrocytes, suggesting that neuroinflammation plays a less causal role in PD than AD. Beyond PD, we find associations between SN DaNs and GABAergic neuron gene expression and multiple neuropsychiatric disorders. Conditional analysis reveals that distinct neuropsychiatric disorders associate with distinct sets of neuron-specific genes but converge onto shared loci within oligodendrocytes and oligodendrocyte precursors. This atlas guides our aetiological understanding by associating SN cell type expression profiles with specific disease risk.


Assuntos
Expressão Gênica , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Encéfalo , Neurônios Dopaminérgicos/metabolismo , Humanos , Microglia/metabolismo , Mitocôndrias/metabolismo , Doenças do Sistema Nervoso/patologia , Substância Negra/patologia , Transcriptoma
5.
J Stroke Cerebrovasc Dis ; 29(7): 104828, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32404284

RESUMO

BACKGROUND: Pathomechanism of secondary degeneration in remote regions after ischemic stroke has not been totally clarified. Contrast-enhanced MRI with injecting Gd-DTPA in cisterna magna (CM) is regarded as an efficient method to measure glymphatic system function in brain. Our research aimed at evaluating glymphatic system changes in secondary degeneration areas by contrast-enhanced MRI. METHODS: Ischemic stroke was induced by left middle cerebral artery occlusion (MCAO) model. A total of 12 Sprague-Dawley rats were randomly divided into three groups: control group with sham operations (n=4), the group of acute phase (1 day after MCAO) (n=4), and the group of subacute phase (7 days after MCAO) (n=4). Contrast-enhanced MRI was performed in 1days or 7days after operations respectively. All rats received an intrathecal injection of Gd-DTPA (2µl/min, totally 20µl) and high-resolution 3D T1-weighted MRI for 6 h. The time course of the signal-to-noise ratio (SNR) in substantia Nigra (SN) and ventral thalamic nucleus (VTN) was evaluated between two hemispheres in all rats. RESULTS: In control group without ischemia, time-to-peak of SNR in SN was earlier than that in VTN. There were no differences of SNR between two hemispheres after intrathecal Gd-DTPA administration. In the group of acute phase, MRI revealed similar time course and time-to-peak of SNR between ipsilateral and contralateral VTN, while a tendency of higher SNR in ipsilateral SN than contralateral SN at 4h, 5h, 6h after Gd-DTPA injection. And time-to-peak of SNR was similar in bilateral SN. In the group of subacute phase, time-to-peak of SNR was similar in bilateral VTN, while longer in ipsilateral SN compared with contralateral side. In addition, SNR in T1WI in ipsilateral was significantly higher than SNR in contralateral SN and VTN at 5h (VTN, P= 0.003; SN, P=0.004) and 6h (VTN, P=0.015; SN, P=0.006) after Gd-DTPA injection. CONCLUSION: Glymphatic system was impaired in ipsilateral SN and VTN after ischemic stroke, which may contribute to neural degeneration.


Assuntos
Meios de Contraste/administração & dosagem , Gadolínio DTPA/administração & dosagem , Sistema Glinfático/diagnóstico por imagem , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Imagem por Ressonância Magnética , Degeneração Neural , Substância Negra/diagnóstico por imagem , Núcleos Ventrais do Tálamo/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Sistema Glinfático/patologia , Sistema Glinfático/fisiopatologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Valor Preditivo dos Testes , Ratos Sprague-Dawley , Razão Sinal-Ruído , Substância Negra/patologia , Substância Negra/fisiopatologia , Fatores de Tempo , Núcleos Ventrais do Tálamo/patologia , Núcleos Ventrais do Tálamo/fisiopatologia
6.
Neurobiol Aging ; 91: 76-87, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32224067

RESUMO

The etiology and pathogenesis of Parkinson's disease (PD) are tightly linked to the gain-of-function of α-synuclein. However, gradual accumulation of α-synuclein aggregates in dopaminergic neurons of substantia nigra pars compacta (SNpc) leads to the depletion of the functional pool of soluble α-synuclein, and therefore, creates loss-of-function conditions, particularly in presynaptic terminals of these neurons. Studies of how this late-onset depletion of a protein involved in many important steps of neurotransmission contributes to PD progression and particularly, to worsening the nigrostriatal pathology at late stages of the disease are limited and obtained data, are controversial. Recently, we produced a mouse line for conditional knockout of the gene encoding α-synuclein, and here we used its tamoxifen-inducible pan-neuronal inactivation to study consequences of the adult-onset (from the age of 6 months) and late-onset (from the age of 12 months) α-synuclein depletion to the nigrostriatal system. No significant changes of animal balance/coordination, the number of dopaminergic neurons in the SNpc and the content of dopamine and its metabolites in the striatum were observed after adult-onset α-synuclein depletion, but in aging (18-month-old) late-onset depleted mice we found a significant reduction of major dopamine metabolites without changes to the content of dopamine itself. Our data suggest that this might be caused, at least partially, by reduced expression of aldehyde dehydrogenase ALDH1a1 and could lead to the accumulation of toxic intermediates of dopamine catabolism. By extrapolating our findings to a potential clinical situation, we suggest that therapeutic downregulation of α-synuclein expression in PD patients is a generally safe option as it should not cause adverse side effects on the functionality of their nigrostriatal system. However, if started in aged patients, this type of therapy might trigger slight functional changes of the nigrostriatal system with potentially unwanted additive effect to already existing pathology.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Técnicas de Inativação de Genes , Doença de Parkinson/etiologia , Doença de Parkinson/genética , Substância Negra/metabolismo , Substância Negra/patologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , /genética , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Regulação para Baixo , Expressão Gênica/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Doença de Parkinson/terapia , Retinal Desidrogenase/genética , Retinal Desidrogenase/metabolismo , Transmissão Sináptica/genética
7.
Ann Neurol ; 87(6): 853-868, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32167609

RESUMO

OBJECTIVE: Neuronal loss in the substantia nigra pars compacta (SNpc) in Parkinson disease (PD) is not uniform, as dopamine neurons from the ventral tier are lost more rapidly than those of the dorsal tier. Identifying the intrinsic differences that account for this differential vulnerability may provide a key for developing new treatments for PD. METHODS: Here, we compared the RNA-sequenced transcriptomes of ~100 laser captured microdissected SNpc neurons from each tier from 7 healthy controls. RESULTS: Expression levels of dopaminergic markers were similar across the tiers, whereas markers specific to the neighboring ventral tegmental area were virtually undetected. After accounting for unwanted sources of variation, we identified 106 differentially expressed genes (DEGs) between the SNpc tiers. The genes higher in the dorsal/resistant SNpc tier neurons displayed coordinated patterns of expression across the human brain, their protein products had more interactions than expected by chance, and they demonstrated evidence of functional convergence. No significant shared functionality was found for genes higher in the ventral/vulnerable SNpc tier. Surprisingly but importantly, none of the identified DEGs was among the familial PD genes or genome-wide associated loci. Finally, we found some DEGs in opposite tier orientation between human and analogous mouse populations. INTERPRETATION: Our results highlight functional enrichments of vesicular trafficking, ion transport/homeostasis and oxidative stress genes showing higher expression in the resistant neurons of the SNpc dorsal tier. Furthermore, the comparison of gene expression variation in human and mouse SNpc populations strongly argues for the need of human-focused omics studies. ANN NEUROL 2020;87:853-868.


Assuntos
Neurônios Dopaminérgicos/patologia , Mesencéfalo/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Transcriptoma , Animais , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Voluntários Saudáveis , Humanos , Camundongos , RNA/genética , Substância Negra/patologia , Área Tegmentar Ventral/patologia
8.
Nat Commun ; 11(1): 941, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071304

RESUMO

Oxidative stress is a major pathogenic mechanism in Parkinson's disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. GSH level is decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. In addition we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. We conclude that dimerizing PKM2 may be a potential target for PD treatment.


Assuntos
Glutationa/biossíntese , Intoxicação por MPTP/patologia , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/administração & dosagem , Piruvato Quinase/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Astrócitos , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Dopamina/metabolismo , Neurônios Dopaminérgicos , Intoxicação por MPTP/diagnóstico , Intoxicação por MPTP/tratamento farmacológico , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Cultura Primária de Células , Multimerização Proteica/efeitos dos fármacos , Piridoxina/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Receptores de Dopamina D2/genética , Substância Negra/citologia , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Ativação Transcricional
9.
J Neurosci ; 40(9): 1975-1986, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32005765

RESUMO

Mitochondrial dysfunction is critically involved in Parkinson's disease, characterized by loss of dopaminergic neurons (DaNs) in the substantia nigra (SNc), whereas DaNs in the neighboring ventral tegmental area (VTA) are much less affected. In contrast to VTA, SNc DaNs engage calcium channels to generate action potentials, which lead to oxidant stress by yet unknown pathways. To determine the molecular mechanisms linking calcium load with selective cell death in the presence of mitochondrial deficiency, we analyzed the mitochondrial redox state and the mitochondrial membrane potential in mice of both sexes with genetically induced, severe mitochondrial dysfunction in DaNs (MitoPark mice), at the same time expressing a redox-sensitive GFP targeted to the mitochondrial matrix. Despite mitochondrial insufficiency in all DaNs, exclusively SNc neurons showed an oxidized redox-system, i.e., a low reduced/oxidized glutathione (GSH-GSSG) ratio. This was mimicked by cyanide, but not by rotenone or antimycin A, making the involvement of reactive oxygen species rather unlikely. Surprisingly, a high mitochondrial inner membrane potential was maintained in MitoPark SNc DaNs. Antagonizing calcium influx into the cell and into mitochondria, respectively, rescued the disturbed redox ratio and induced further hyperpolarization of the inner mitochondrial membrane. Our data therefore show that the constant calcium load in SNc DaNs is counterbalanced by a high mitochondrial inner membrane potential, even under conditions of severe mitochondrial dysfunction, but triggers a detrimental imbalance in the mitochondrial redox system, which will lead to neuron death. Our findings thus reveal a new mechanism, redox imbalance, which underlies the differential vulnerability of DaNs to mitochondrial defects.SIGNIFICANCE STATEMENT Parkinson's disease is characterized by the preferential degeneration of dopaminergic neurons (DaNs) of the substantia nigra pars compacta (SNc), resulting in the characteristic hypokinesia in patients. Ubiquitous pathological triggers cannot be responsible for the selective neuron loss. Here we show that mitochondrial impairment together with elevated calcium burden destabilize the mitochondrial antioxidant defense only in SNc DaNs, and thus promote the increased vulnerability of this neuron population.


Assuntos
Antioxidantes/metabolismo , Cálcio/toxicidade , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Substância Negra/metabolismo , Substância Negra/patologia , Animais , Calbindina 1/metabolismo , Morte Celular , Cianetos/toxicidade , Feminino , Masculino , Potencial da Membrana Mitocondrial , Camundongos , Membranas Mitocondriais/metabolismo , Oxirredução , Estresse Oxidativo , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/patologia
10.
FASEB J ; 34(1): 1679-1694, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914683

RESUMO

Increased pro-inflammatory cytokine levels and proliferation of activated microglia have been found in Parkinson's disease (PD) patients and animal models of PD, suggesting that targeting of the microglial inflammatory response may result in neuroprotection in PD. Microglial proliferation is regulated by many factors, but colony stimulating factor-1 receptor (CSF1R) has emerged as a primary factor. Using data mining techniques on existing microarray data, we found that mRNA expression of the CSF1R ligand, CSF-1, is increased in the brain of PD patients compared to controls. In two different neurotoxic mouse models of PD, acute MPTP and sub-chronic LPS treatment, mRNA and protein levels of CSF1R and CSF-1 were significantly increased. Treatment with the CSF1R inhibitor GW2580 significantly attenuated MPTP-induced CSF1R activation and Iba1-positive cell proliferation, without a reduction of the basal Iba1-positive population in the substantia nigra. GW2580 treatment also significantly decreased mRNA levels of pro-inflammatory factors, without alteration of anti-inflammatory mediators, and significantly attenuated the MPTP-induced loss of dopamine neurons and motor behavioral deficits. Importantly, these effects were observed in the absence of overt microglial depletion, suggesting that targeting CSF1R signaling may be a viable neuroprotective strategy in PD that disrupts pro-inflammatory signaling, but maintains the beneficial effects of microglia.


Assuntos
Anisóis/farmacologia , Anti-Inflamatórios/farmacologia , Proliferação de Células/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pirimidinas/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Transdução de Sinais/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia
11.
Ann Neurol ; 87(3): 329-338, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31953875

RESUMO

OBJECTIVE: Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system. METHODS: This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateral disease (n = 12) and matched normal controls (n = 12) using in vivo high-resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen. RESULTS: A group-by-brain region interaction effect (F10, 22 = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (-45%; p < 0.001), red nucleus (-31%; p = 0.03), and locus coeruleus (-17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (-17%; p < 0.005) and nonsignificant findings in the putamen (-4%; p = 0.06). INTERPRETATION: This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329-338.


Assuntos
Diagnóstico Precoce , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Putamen/patologia , Substância Negra/patologia , Sinapses/patologia , Autorradiografia , Estudos de Casos e Controles , Feminino , Neuroimagem Funcional , Humanos , Locus Cerúleo/patologia , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons , Putamen/metabolismo , Piridinas , Pirrolidinas , Núcleo Rubro/patologia , Substância Negra/metabolismo
12.
Exp Neurol ; 327: 113211, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31987834

RESUMO

Transsynaptic anterograde and retrograde degeneration of neurons and neural fibers are assumed to trigger local excitotoxicity and inflammatory processes. These processes in turn are thought to drive exo-focal neurodegeneration in remote areas connected to the infarcted tissue after ischemic stroke. In the case of middle cerebral artery occlusion (MCAO), in which striato-nigral connections are affected, the hypothesis of inflammation-induced remote neurodegeneration is based on the temporal dynamics of an early appearance of inflammatory markers in midbrain followed by dopaminergic neuronal loss. To test the hypothesis of a direct transsynaptic mediation of secondary exo-focal post-ischemic neurodegeneration, we used a photochemical induction of a stroke (PTS) in Sprague-Dawley rats restricted to motor cortex (MC), thereby sparing the striatal connections to dopaminergic midbrain nuclei. To dissect the temporal dynamics of post-ischemic neurodegeneration, we analyzed brain sections harvested at day 7 and 14 post stroke. Here, an unexpectedly pronounced and widespread loss of dopaminergic neurons occurred 14 days after stroke also affecting dopaminergic nuclei that are not directly coupled to MC. Since the pattern of neurodegeneration in case of a pure motor stroke is similar to a major stroke including the striatum, it is unlikely that direct synaptic coupling is a prerequisite for delayed secondary exo-focal post ischemic neurodegeneration. Furthermore, dopaminergic neurodegeneration was already detected by Fluoro-Jade C staining at day 7, coinciding with a solely slight inflammatory response. Thus, inflammation cannot be assumed to be the primary driver of exo-focal post-ischemic cell death. Moreover, nigral substance P (SP) expression indicated intact striato-nigral innervation after PTS, whereas opposing effects on SP expression after striatal infarcts argue against a critical role of SP in neurodegenerative or inflammatory processes during exo-focal neurodegeneration.


Assuntos
Neurônios Dopaminérgicos/patologia , Mesencéfalo/patologia , Córtex Motor/patologia , Degeneração Neural/patologia , Acidente Vascular Cerebral/patologia , Animais , Neurônios Dopaminérgicos/metabolismo , Masculino , Mesencéfalo/metabolismo , Córtex Motor/metabolismo , Degeneração Neural/metabolismo , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/metabolismo , Substância P/metabolismo , Substância Negra/metabolismo , Substância Negra/patologia
13.
Ann Neurol ; 87(2): 302-312, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31773773

RESUMO

OBJECTIVE: The pallidonigroluysian (PNL) system, the primary component of corticosubcortical circuits, is generally spared in amyotrophic lateral sclerosis (ALS). We evaluated the clinicopathological features of an unusual form of ALS with PNL degeneration (PNLD) and assessed whether ALS with PNLD represents a distinct ALS subtype. METHODS: From a cohort of 97 autopsied cases of sporadic ALS with phosphorylated 43kDa TAR DNA-binding protein (TDP-43) inclusions, we selected those with PNLD and analyzed their clinicopathological features. RESULTS: Eleven cases (11%) that showed PNLD were divided into 2 subtypes depending on the lesion distribution: (1) extensive type (n = 6), showing widespread TDP-43 pathology and multisystem degeneration, both involving the PNL system; and (2) limited type (n = 5), showing selective PNL and motor system involvement, thus being unclassifiable in terms of Brettschneider's staging or Nishihira's typing of ALS. The limited type showed a younger age at onset and predominant PNLD that accounted for the early development of extrapyramidal signs. The limited type exhibited the heaviest pathology in the subthalamus and external globus pallidus, suggesting that TDP-43 inclusions propagated via indirect or hyperdirect pathways, unlike ALS without PNLD, where the direct pathway is considered to convey TDP-43 aggregates from the cerebral cortex to the substantia nigra. INTERPRETATION: The PNL system can be involved in the disease process of ALS, either nonselectively as part of multisystem degeneration, or selectively. ALS with selective involvement of the PNL and motor systems exhibits unique clinicopathological features and TDP-43 propagation routes, thus representing a distinct subtype of ALS. ANN NEUROL 2020;87:302-312.


Assuntos
Esclerose Amiotrófica Lateral/patologia , Globo Pálido/patologia , Substância Negra/patologia , Núcleo Subtalâmico/patologia , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/classificação , Feminino , Humanos , Corpos de Inclusão/patologia , Masculino , Pessoa de Meia-Idade , Vias Neurais/patologia , Proteinopatias TDP-43/classificação , Proteinopatias TDP-43/patologia
14.
Mol Cell Biochem ; 465(1-2): 89-102, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31820278

RESUMO

Parkinson's disease (PD) is the second common age-related neurodegenerative disease. It is characterized by control loss of voluntary movements control, resting tremor, postural instability, bradykinesia, and rigidity. The aim of the present work is to evaluate curcumin, niacin, dopaminergic and non-dopaminergic drugs in mice model of Parkinson's disease through behavioral, biochemical, genetic and histopathological observations. Mice treated with rotenone rerecorded significant increase in adenosine A2A receptor (A2AR) gene expression, α synuclein, acetylcholinesterase (AchE), malondialdehyde (MDA), angiotensin-II (Ang-II), c-reactive protein (CRP), interleukin-6 (IL-6), caspase-3 (Cas-3) and DNA fragmentation levels as compared with the control group. While, significant decrease in dopamine (DA), norepinephrine (NE), serotonin (5-HT), superoxide dismutase (SOD), reduced glutathione (GSH), ATP, succinate and lactate dehydrogenases (SDH &LDH) levels were detected. Treatment with curcumin, niacin, adenosine A2AR antagonist; ZM241385 and their combination enhanced the animals' behavior and restored all the selected parameters with variable degrees of improvement. The brain histopathological features of hippocampal and substantia nigra regions confirmed our results. In conclusion, the combination of curcumin, niacin and ZM241385 recorded the most potent treatment effect in Parkinsonism mice followed by ZM241385, as a single treatment. ZM241385 succeeded to antagonize adenosine A2A receptor by diminishing its gene expression and ameliorating all biochemical parameters under investigation. The newly investigated agent; ZM241385 has almost the same pattern of improvement as the classical drug; Sinemet®. This could shed the light to the need of detailed studies on ZM241385 for its possible role as a promising treatment against PD. Additionally, food supplements such as curcumin and niacin were effective in Parkinson's disease eradication.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Curcumina/farmacologia , Niacina/farmacologia , Doença de Parkinson Secundária , Receptor A2A de Adenosina/metabolismo , Rotenona/administração & dosagem , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Rotenona/farmacologia , Substância Negra/metabolismo , Substância Negra/patologia
15.
Life Sci ; 240: 117091, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760102

RESUMO

Mounting evidences indicated that elevated iron levels in the substantia nigra (SN) have been concerned as the underlying mechanisms of neurodegenerative diseases, including Parkinson's disease (PD). The present study used the 1-Methyl-4-phenyl-1, 2, 3, 6 -tetrahydropyridine (MPTP)-treated cynomolgus monkeys for PD to evaluate the usability of SWI for assessing iron deposition in the cerebral nuclei of PD. The results showed that susceptibility-weighted imaging (SWI) phase values of the ipsilateral (MPTP-lesion side) SN of MPTP-treated monkeys were lower than those in the contralateral SN of MPTP-treated monkeys and the same side of Control monkeys, suggesting that iron deposition were elevated in the affected side SN of MPTP-treated monkeys. Whereas MPTP has not effects on the SWI phase values in other detected brain regions of monkeys, including red nucleus (RN), putamen (PUT) and caudate nucleus (CA). Furthermore, ICP-MS results showed that MPTP increased the iron levels in MPTP injection side, but no in the ipsilateral striatum. Additionally, MPTP treatment did not affect the calcium and manganese levels in the detected brain regions of monkeys. However, Pearson correlation analysis results indicated that there were not relationship between SWI phase values in MPTP-lesion side of SN with the behavioral score, tyrosine hydroxylase (TH)-positive cells number and iron levels in the MPTP-lesion side of midbrain. Taken together, the results confirm the involvement of SN iron accumulations in the MPTP-treated monkey models for PD, and indirectly verify the usability of SWI for the measurement of iron deposition in the cerebral nuclei of PD.


Assuntos
Ferro/metabolismo , Intoxicação por MPTP/metabolismo , Transtornos Parkinsonianos/metabolismo , Animais , Comportamento Animal , Encéfalo/diagnóstico por imagem , Cálcio/metabolismo , Intoxicação por MPTP/diagnóstico por imagem , Macaca fascicularis , Imagem por Ressonância Magnética , Masculino , Manganês/metabolismo , Espectrometria de Massas , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/diagnóstico por imagem , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo
16.
Behav Pharmacol ; 31(1): 45-60, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31625972

RESUMO

Baseline locomotion and behavioral traits in the common marmoset Parkinson's disease model were examined to provide basic information for preclinical evaluations of medical treatments. A single regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine at a cumulative dose of 5 mg/kg as the free base over three consecutive days was administered subcutaneously to 10 marmosets. Data obtained from these marmosets were compared to pre-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine levels or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine free marmosets. After the single regimen, reduced daily locomotion, a measure of immobility (a primary sign of Parkinsonism), was observed for more than a year. A moving tremor was also observed by visual inspection during this period. When apomorphine (0.13 mg/kg, s.c.) was administered, either right or left circling behavior was observed in a cylindrical chamber in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine marmosets, suggestive of unequal neural damage between the two brain hemispheres to different extents. MRI revealed that T1 relaxation time in the right substantia nigra correlated with right circling in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine marmosets. Histology was supportive of dopaminergic neural loss in the striatum. These results increase our understanding of the utility and limitations of the Parkinson's disease model in marmosets with a single 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine regimen, and provide reference data for efficacious preclinical evaluations.


Assuntos
Locomoção/fisiologia , Doença de Parkinson/patologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Callithrix/fisiologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Transtornos Parkinsonianos/patologia , Substância Negra/patologia , Tremor/induzido quimicamente
17.
Mol Neurobiol ; 57(2): 806-822, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31473904

RESUMO

Parkinson's disease is characterized by a loss of dopaminergic neurons in the ventral midbrain. This disease is diagnosed when around 50% of these neurons have already died; consequently, therapeutic treatments start too late. Therefore, an urgent need exists to find new targets involved in the onset and progression of the disease. Phosphodiesterase 7 (PDE7) is a key enzyme involved in the degradation of intracellular levels of cyclic adenosine 3', 5'-monophosphate in different cell types; however, little is known regarding its role in neurodegenerative diseases, and specifically in Parkinson's disease. We have previously shown that chemical as well as genetic inhibition of this enzyme results in neuroprotection and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson's disease. Here, we have used in vitro and in vivo models of Parkinson's disease to study the regulation of PDE7 protein levels. Our results show that PDE7 is upregulated after an injury both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures and after lipopolysaccharide or 6-hidroxydopamine injection in the Substantia nigra pars compacta of adult mice. PDE7 increase takes place mainly in degenerating dopaminergic neurons and in microglia cells. This enhanced expression appears to be direct since 6-hydroxydopamine and lipopolysaccharide increase the expression of a 962-bp fragment of its promoter. Taking together, these results reveal an essential function for PDE7 in the pathways leading to neurodegeneration and inflammatory-mediated brain damage and suggest novel roles for PDE7 in neurodegenerative diseases, specifically in PD, opening the door for new therapeutic interventions.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Doença de Parkinson/enzimologia , Doença de Parkinson/patologia , Animais , Apoptose , Linhagem Celular , Células Cultivadas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/genética , Modelos Animais de Doenças , Neurônios Dopaminérgicos/enzimologia , Neurônios Dopaminérgicos/patologia , Embrião de Mamíferos/enzimologia , Humanos , Masculino , Mesencéfalo/enzimologia , Mesencéfalo/patologia , Neuroglia/enzimologia , Neuroglia/patologia , Oxidopamina , Regiões Promotoras Genéticas/genética , Ratos Wistar , Substância Negra/enzimologia , Substância Negra/patologia
18.
J Cell Physiol ; 235(2): 869-879, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31232473

RESUMO

Lack of dopamine production and neurodegeneration of dopaminergic neurons in the substantia nigra are considered as the major characteristics of Parkinson's disease, a prevalent movement disorder worldwide. DJ-1 mutation leading to loss of its protein functions is a genetic factor of PD. In this study, our results illustrated that DJ-1 can directly interact with Ca2+ /calmodulin-dependent protein kinase kinase ß (CaMKKß) and modifies the cAMP-responsive element binding protein 1 (CREB1) activity, thus regulates tyrosine hydroxylase (TH) expression. In Dj-1 knockout mouse substantia nigra, the levels of TH and the phosphorylation of CREB1 Ser133 are significantly decreased. Moreover, Dj-1 deficiency suppresses the phosphorylation of CaMKIV (Thr196/200) and CREB1 (Ser133), subsequently inhibits TH expression in vitro. Furthermore, Knockdown of Creb1 abolishes the effects of DJ-1 on TH regulation. Our data reveal a novel pathway in which DJ-1 regulates CaMKKß/CaMKIV/CREB1 activities to facilitate TH expression.


Assuntos
Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Doença de Parkinson/patologia , Proteína Desglicase DJ-1/metabolismo , Tirosina 3-Mono-Oxigenase/biossíntese , Animais , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Células HEK293 , Células HeLa , Humanos , Camundongos , Camundongos Knockout , Fosforilação , Transdução de Sinais , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo
19.
J Neuropathol Exp Neurol ; 79(1): 86-101, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31803912

RESUMO

Our previous postmortem studies on neonates with neuropathological injury of perinatal hypoxia/ischemia (PHI) showed a dramatic reduction of tyrosine hydroxylase expression (dopamine synthesis enzyme) in substantia nigra (SN) neurons, with reduction of their cellular size. In order to investigate if the above observations represent an early stage of SN degeneration, we immunohistochemically studied the expression of cleaved caspase-3 (CCP3), apoptosis inducing factor (AIF), and DNA fragmentation by using terminal deoxynucleotidyltransferase-mediated dUTP-biotin 3'-end-labeling (TUNEL) technique in the SN of 22 autopsied neonates (corrected age ranging from 34 to 46.5 gestational weeks), in relation to the severity/duration of PHI injury, as estimated by neuropathological criteria. No CCP3-immunoreactive neurons and a limited number of apoptotic TUNEL-positive neurons with pyknotic characteristics were found in the SN. Nuclear AIF staining was revealed only in few SN neurons, indicating the presence of early signs of AIF-mediated degeneration. By contrast, motor neurons of the oculomotor nucleus showed higher cytoplasmic AIF expression and nuclear translocation, possibly attributed to the combined effect of developmental processes and increased oxidative stress induced by antemortem and postmortem factors. Our study indicates the activation of AIF, but not CCP3, in the SN and oculomotor nucleus of the human neonate in the developmentally critical perinatal period.


Assuntos
Apoptose , Biomarcadores/análise , Hipóxia-Isquemia Encefálica/patologia , Mesencéfalo/patologia , Fator de Indução de Apoptose/análise , Autopsia , Caspase 3/análise , Fragmentação do DNA , Feminino , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Neurônios Motores/patologia , Nervo Oculomotor/patologia , Estresse Oxidativo , Substância Negra/patologia
20.
Mol Neurobiol ; 57(2): 685-697, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31446549

RESUMO

Loss of nigrostriatal projections by axonal degeneration is a key early event in Parkinson's disease (PD) pathophysiology, being accountable for the lack of dopamine in the nigrostriatal system and resulting in motor symptoms such as bradykinesia, rigidity, and tremor. Since autophagy is an important mechanism contributing to axonal degeneration, we aimed to evaluate the effects of competitive autophagy inhibition in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD in vivo. Adeno-associated viral vector (AAV)-mediated overexpression of a dominant-negative form of the unc-51 like autophagy-initiating kinase (ULK1.DN) in the substantia nigra was induced 3 weeks before MPTP treatment. Analysis of motor behavior demonstrated a significant improvement of ULK1.DN expressing mice after MPTP treatment. Immunohistochemical analyses of dopaminergic nigral neurons and nigrostriatal projections revealed a significant protection from MPTP-induced neurotoxicity after ULK1.DN expression. Western blot analysis linked these findings to an activation of mTOR signaling. Taken together, our results indicate that expression of ULK1.DN can attenuate MPTP-induced axonal neurodegeneration, suggesting that ULK1 could be a promising novel target in the treatment of PD.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Dependovirus/metabolismo , Genes Dominantes , Atividade Motora , Neurônios/enzimologia , Neurônios/patologia , Doença de Parkinson/enzimologia , Doença de Parkinson/fisiopatologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Comportamento Animal , Sobrevivência Celular , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Células HEK293 , Humanos , Masculino , Metaboloma , Camundongos Endogâmicos C57BL , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo
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