Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.639
Filtrar
1.
Medicine (Baltimore) ; 99(45): e23060, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157962

RESUMO

Parkinsonian syndromes include typical cases of idiopathic Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) associated with cognitive and vegetative disorders, which are more challenging to diagnose. The aim of this study was to assess -the value of dual-tracer imaging 6-fluoro-(18F)-L-DOPA (FDOPA) and fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), performed in routine patients demonstrating extrapyramidal signs and cognitive complains, for the diagnosis and management of parkinsonian syndromes.We retrospectively included 143 consecutive patients who underwent both FDOPA PET/CT (for the evaluation of parkinsonism) and FDG PET/CT (for the evaluation of cognitive complaints) in the same institution. The suspected clinical diagnosis before imaging and the final post-imaging diagnosis were collected by a dedicated questionnaire.FDOPA was pathological in 90.2% of cases, including 74.1% of PD, 3.5% of parkinsonian dementia and 7% of APS. FDG was normal or near normal in 58.7% of patients. A pattern of diffuse cortical hypometabolism was observed in the remaining patients, more frequently in APS than in PD patients (P = .001). Importantly, in 7.7% of cases dual-tracer PET/CT allowed to decide between several diagnostic hypotheses and led to a new diagnosis in 14.0%. Therefore, the management of these patients was modified, with clinical re-evaluation in a specialized unit and a control of neuropsychological tests and imaging.Dual-tracer PET/CT imaging may be a precious help in the diagnosis and management of parkinsonian syndromes.


Assuntos
Fluordesoxiglucose F18/metabolismo , Transtornos Parkinsonianos/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Demência/diagnóstico , Demência/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/normas , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Administração dos Cuidados ao Paciente/métodos , Estudos Retrospectivos
2.
Nat Commun ; 11(1): 4958, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009395

RESUMO

Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be determined by plasma membrane GABA uptake transporters (GATs) located on astrocytes and neurons. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs are downregulated, tonic GABAergic inhibition of DA release augmented, and nigrostriatal GABA co-release attenuated. These data define previously unappreciated and important roles for GATs and astrocytes in supporting DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.


Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Regulação para Baixo , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Transtornos Parkinsonianos/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Astrócitos/metabolismo , Membrana Celular/metabolismo , Modelos Animais de Doenças , Glutamato Descarboxilase/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Núcleo Accumbens/metabolismo
3.
J Neurosci ; 40(18): 3675-3691, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32238479

RESUMO

The transcription factor Nurr1 has been identified to be ectopically induced in the striatum of rodents expressing l-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression. We used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) male rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with l-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single-unit recordings and dendritic spine analyses on striatal medium spiny neurons (MSNs) in drug-naïve rAAV-injected male parkinsonian rats. rAAV-GFP injected LID-resistant hemi-parkinsonian Lewis rats displayed mild LID and no induction of striatal Nurr1 despite receiving a high dose of l-DOPA. However, Lewis rats overexpressing Nurr1 developed severe LID. Nurr1 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in l-DOPA-naïve rats striatal rAAV-Nurr1 overexpression (1) increased cortically-evoked firing in a subpopulation of identified striatonigral MSNs, and (2) altered spine density and thin-spine morphology on striatal MSNs; both phenomena mimicking changes seen in dyskinetic rats. Finally, we provide postmortem evidence of Nurr1 expression in striatal neurons of l-DOPA-treated PD patients. Our data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.SIGNIFICANCE STATEMENT The transcription factor Nurr1 is ectopically induced in striatal neurons of rats exhibiting levodopa-induced dyskinesia [LID; a side-effect to dopamine replacement strategies in Parkinson's disease (PD)]. Here we asked whether Nurr1 is causing LID. Indeed, rAAV-mediated expression of Nurr1 in striatal neurons was sufficient to overcome LID-resistance, and Nurr1 agonism exacerbated LID severity in dyskinetic rats. Moreover, we found that expression of Nurr1 in l-DOPA naïve hemi-parkinsonian rats resulted in the formation of morphologic and electrophysiological signatures of maladaptive neuronal plasticity; a phenomenon associated with LID. Finally, we determined that ectopic Nurr1 expression can be found in the putamen of l-DOPA-treated PD patients. These data suggest that striatal Nurr1 is an important mediator of the formation of LID.


Assuntos
Corpo Estriado/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/toxicidade , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Transtornos Parkinsonianos/metabolismo , Idoso , Animais , Corpo Estriado/efeitos dos fármacos , Discinesia Induzida por Medicamentos/patologia , Feminino , Humanos , Masculino , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Ratos Sprague-Dawley
4.
Toxicology ; 436: 152437, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32169474

RESUMO

Mild cognitive impairment in Parkinson's disease (PD-MCI) is considered as a nonmotor clinical symptom in Parkinson's disease (PD). Microglia-mediated inflammation contributes to cognitive function impairment. Poloxamer 188 (P188) is an amphipathic polymer which has cytoprotective effect in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neurons degeneration in PD. But whether P188 could ameliorate cognitive impairment in PD is still illusive. In the present study, we showed in a mouse model that paraquat (10 mg/kg) and maneb (30 mg/kg) (P + M) treatment intraperitoneally twice a week for 6 consecutive weeks resulted in cognitive deficits and synapse loss in hippocampus, together with DA neuron damage in the substantia nigra pars compacta (SNpc). P188 (0.8 g/kg) injection via tail vein 30 min after P + M administration significantly restored DA neuron numbers in SNpc and synapse density in hippocampus, and alleviated P + M-mediated cognitive function impairment in novel object recognition task and morris water maze task (MWM). Pathological synapse loss might be attributed to increased microglial phagocytic activity and cell density, and P188 prevented P + M-induced phagocytic state changes of microglia, such as increase in cell body size and decrease in process length, and upregulated microglia abundance in hippocampus. Consistently, P188 attenuated P + M-mediated increased mRNA levels of microglia proliferation related CSF1r and CSF2ra, microglial engulfment associated CD68, ICAM1, and ICAM2, and pro-inflammatory IL-6, IL-1ß, CD11b, and TNF-α in hippocampus. Together, these findings suggest that the biocompatible polymer P188 blunts microglia activation which may promote synaptic loss and exacerbate cognitive function in a mouse model of PD-MCI.


Assuntos
Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Hipocampo/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Parte Compacta da Substância Negra/efeitos dos fármacos , Poloxâmero/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Maneb , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Degeneração Neural , Paraquat , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/psicologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Fagocitose/efeitos dos fármacos , Poloxâmero/farmacocinética , Reconhecimento Psicológico/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia
5.
Neuron ; 105(5): 822-836.e7, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-31899072

RESUMO

Mutations in the GBA1 gene are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1 encodes the lysosomal lipid hydrolase glucocerebrosidase (GCase), and its activity has been linked to accumulation of α-synuclein. The current study systematically examines the relationship between GCase activity and both pathogenic and non-pathogenic forms of α-synuclein in primary hippocampal, cortical, and midbrain neuron and astrocyte cultures, as well as in transgenic mice and a non-transgenic mouse model of PD. We find that reduced GCase activity does not result in aggregation of α-synuclein. However, in the context of extant misfolded α-synuclein, GCase activity modulates neuronal susceptibility to pathology. Furthermore, this modulation does not depend on neuron type but rather is driven by the level of pathological α-synuclein seeds. This study has implications for understanding how GBA1 mutations influence PD pathogenesis and provides a platform for testing novel therapeutics.


Assuntos
Astrócitos/metabolismo , Glucosilceramidase/genética , Neurônios/metabolismo , Transtornos Parkinsonianos/genética , Agregação Patológica de Proteínas/genética , alfa-Sinucleína/metabolismo , Animais , Astrócitos/citologia , Astrócitos/patologia , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Suscetibilidade a Doenças , Predisposição Genética para Doença , Glucosilceramidase/metabolismo , Células HEK293 , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Mesencéfalo/citologia , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Cultura Primária de Células , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Sinucleinopatias/genética , Sinucleinopatias/metabolismo , Sinucleinopatias/patologia
6.
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
7.
Biochim Biophys Acta Mol Basis Dis ; 1866(1): 165581, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672549

RESUMO

Exposure to environmental toxins, including hydrocarbon solvents, increases the risk of developing Parkinson's disease. An emergent hypothesis considers microtubule dysfunction as one of the crucial events in triggering neuronal degeneration in Parkinson's disease. Here, we used 2,5-hexanedione (2,5-HD), the toxic metabolite of n-hexane, to analyse the early effects of toxin-induced neurodegeneration on the cytoskeleton in multiple model systems. In PC12 cells differentiated with nerve growth factor for 5 days, we found that 2,5-HD treatment affected all the cytoskeletal components. Moreover, we observed alterations in microtubule distribution and stability, in addition to the imbalance of post-translational modifications of α-tubulin. Similar defects were also found in vivo in 2,5-HD-intoxicated mice. Interestingly, we also found that 2,5-HD exposure induced significant changes in microtubule stability in human skin fibroblasts obtained from Parkinson's disease patients harbouring mutations in PRKN gene, whereas it was ineffective in healthy donor fibroblasts, suggesting that the genetic background may really make the difference in microtubule susceptibility to this environmental Parkinson's disease-related toxin. In conclusion, by showing the imbalance between dynamic and stable microtubules in hydrocarbon-induced parkinsonism, our data support the crucial role of microtubule defects in triggering neurodegeneration.


Assuntos
Hexanonas/farmacologia , Microtúbulos/efeitos dos fármacos , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Animais , Linhagem Celular , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Camundongos , Microtúbulos/metabolismo , Fatores de Crescimento Neural/metabolismo , Células PC12 , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Ratos , Tubulina (Proteína)/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
8.
Exp Neurol ; 323: 113062, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513786

RESUMO

The excitatory neurotransmitter glutamate is essential in basal ganglia motor circuits and has long been thought to contribute to cell death and degeneration in Parkinson's disease (PD). While previous research has shown a significant role of NMDA and AMPA receptors in both excitotoxicity and PD, the third class of ionotropic glutamate receptors, kainate receptors, have been less well studied. Given the expression of kainate receptor subunits GluK1-GluK3 in key PD-related brain regions, it has been suggested that GluK1-GluK3 may contribute to excitotoxic cell loss. Therefore the neuroprotective potential of the kainate receptor antagonist UBP310 in animal models of PD was investigated in this study. Stereological quantification revealed administration of UBP310 significantly increased survival of dopaminergic and total neuron populations in the substantia nigra pars compacta in the acute MPTP mouse model of PD. In contrast, UBP310 was unable to rescue MPTP-induced loss of dopamine levels or dopamine transporter expression in the striatum. Furthermore, deletion of GluK1, GluK2 or GluK3 had no effect on MPTP or UBP310-mediated effects across all measures. Interestingly, UBP310 did not attenuate cell loss in the midbrain induced by intrastriatal 6-OHDA toxicity. These results indicate UBP310 provides neuroprotection in the midbrain against MPTP neurotoxicity that is not dependent on specific kainate receptor subunits.


Assuntos
Alanina/análogos & derivados , Neurônios Dopaminérgicos/efeitos dos fármacos , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Transtornos Parkinsonianos/metabolismo , Timina/análogos & derivados , Alanina/farmacologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural/metabolismo , Receptores de Ácido Caínico/metabolismo , Timina/farmacologia
9.
J Clin Neurosci ; 71: 217-225, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31883812

RESUMO

The accumulation of α-syn which induce endoplasmic reticulum stress (ERS) and mediate various signaling pathways involved in DA neuronal degeneration, and the apoptosis of dopamine (DA) neurons are pathological markers of Parkinson's disease (PD). High-temperature requirement protein A2 (HtrA2) is synthesized in the endoplasmic reticulum, and the expression level of HtrA2 can be upregulated by drugs or by unfolded proteins. Ucf-101 is a specific inhibitor of HtrA2, and studies have shown that Ucf-101 reduced apoptosis in PC12 cells. Our study showed that PC12 cells treated with 60 µM 6-OHDA for 24 h had significantly decreased cell viability compared to that of controls. A low concentration (2.5 µM) of Ucf-101 decreased the apoptosis rate of the PD cell model, but a high concentration (≥10 µM) increased the apoptosis rate, compared to that of controls. 6-OHDA upregulated the expression of HtrA2, α-syn, CHOP, Grp78 and active caspase-3 and reduced the levels of TH and XIAP. Ucf-101 reduced the level of ERS and apoptosis bothin vivoandin vitro. The ratio of p-GSK3ß (Tyr216 to Ser9) increased in PD rats. However, Ucf-101 down-regulated the activation of GSK3ß and activated the Wnt/ß-catenin pathway that was caused by 6-OHDA. Ucf-101 activated the Wnt/ß-catenin pathway and significantly attenuated 6-OHDA-induced neurotoxicity, which was related to the inhibition of ERS and the reduction of the apoptosis rate of PC12 cells and DA neurons in the midbrain of PD rats. Ucf-101 has certain neuroprotective effects.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos , Pirimidinonas/farmacologia , Tionas/farmacologia , Via de Sinalização Wnt/fisiologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Células PC12 , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Ratos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina
10.
Exp Neurol ; 323: 113081, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655049

RESUMO

Phosphatase and tensin homolog (PTEN)-induced kinase 1 (Pink1) is involved in mitochondrial quality control, which is essential for maintaining energy production and minimizing oxidative damage from dysfunctional/depolarized mitochondria. Pink1 mutations are the second most common cause of autosomal recessive Parkinson's disease (PD). In addition to characteristic motor impairments, PD patients also commonly exhibit cognitive impairments. As the hippocampus plays a prominent role in cognition, we tested if loss of Pink1 in mice influences learning and memory. While wild-type mice were able to perform a contextual discrimination task, age-matched Pink1 knockout (Pink1-/-) mice showed an impaired ability to differentiate between two similar contexts. Similarly, Pink1-/- mice performed poorly in a delayed alternation task as compared to age-matched controls. Poor performance in these cognitive tasks was not the result of overt hippocampal pathology. However, a significant reduction in hippocampal tyrosine hydroxylase (TH) protein levels was detected in the Pink1-/- mice. This decrease in hippocampal TH levels was also associated with reduced DOPA decarboxylase and dopamine D2 receptor levels, but not post-synaptic dopamine D1 receptor levels. These presynaptic changes appeared to be selective for dopaminergic fibers as hippocampal dopamine beta hydroxylase, choline acetyltransferase, and tryptophan hydroxylase levels were unchanged in Pink1-/- mice. Administration of the dopamine D1 receptor agonist SKF38393 to Pink1-/- mice was found to improve performance in the context discrimination task. Taken together, our results show that Pink1 loss may alter dopamine signaling in the hippocampus, which could be a contributing mechanism for the observed learning and memory impairments.


Assuntos
Hipocampo/metabolismo , Aprendizagem/fisiologia , Memória/fisiologia , Proteínas Quinases/deficiência , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Aprendizagem/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transtornos Parkinsonianos/metabolismo , Receptores de Dopamina D1/metabolismo
11.
Biochemistry (Mosc) ; 84(11): 1359-1374, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760923

RESUMO

The review summarizes the data of our research and published studies on the ubiquitination of brain mitochondrial proteins and its changes during the development of experimental parkinsonism and administration of the neuroprotector isatin (indole-2,3-dione) with special attention to the mitochondrial ubiquitin-conjugating system and location of ubiquitinated proteins in these organelles. Incubation of brain mitochondrial fraction with biotinylated ubiquitin in vitro resulted in the incorporation of biotinylated ubiquitin in both mitochondrial and mitochondria-associated proteins. According to the interactome analysis, the identified non-ubiquitinated proteins are able to form tight complexes with ubiquitinated proteins or their partners and components of mitochondrial membranes, in which interactions of ubiquitin chains with the ubiquitin-binding protein domains play an important role. The studies of endogenous ubiquitination in the total brain mitochondrial fraction of C57Bl mice performed in different laboratories have shown that mitochondrial proteins represent about 30% of all ubiquitinated proteins. However, comparison of brain subproteomes of mitochondrial ubiquitinated proteins reported in the literature revealed significant differences both in their composition and involvement of identified ubiquitinated proteins in biological processes listed in the Gene Ontology database. The development of experimental parkinsonism in C57Bl mice induced by a single-dose administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in a decrease in the total number of mitochondrial ubiquitinated proteins and increase in the number of oxidized mitochondrial proteins containing the ubiquitin signature (K-ε-GG). Comparison of ubiquitinated proteins associated with the mouse brain mitochondrial fraction and mouse brain mitochondrial proteins bound to the proteasome ubiquitin receptor (Rpn10 subunit) did not reveal any common proteins. This suggests that ubiquitination of brain mitochondrial proteins is not directly related to their degradation in the proteasomes. Proteomic profiling of brain isatin-binding proteins identified enzymes involved in the ubiquitin-conjugating system functioning. Mapping of the identified isatin-binding proteins to known metabolic pathways indicates their participation in the parkin (E3 ubiquitin ligase)-associated pathway (CH000000947). The functional links involving brain mitochondrial ubiquitinated proteins were found only in the group of animals with the MPTP-induced parkinsonism, but not in animals treated with MPTP/isatin or isatin only. This suggests that the neuroprotective effect of isatin may be associated with the impaired functional relationships of proteins targeted to subsequent degradation.


Assuntos
Encéfalo/metabolismo , Transtornos Parkinsonianos/patologia , Ubiquitina/metabolismo , Animais , Autofagia , Redes e Vias Metabólicas , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/veterinária , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitinação
12.
Handb Clin Neurol ; 165: 155-177, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31727210

RESUMO

Progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD) are forms of parkinsonism. PSP and CBD are 4R tauopathies and clinicopathologic overlaps exist between these two disorders. Neuropsychiatric symptoms including apathy, depression, anxiety are common features in patients with PSP and CBD. Disinhibition and impulsive behavior are also frequently observed in PSP patients, whereas hallucinations are seen only occasionally. Severe derangement in several neurotransmitter systems may account for behavioral symptoms observed in PSP and CBD, but substitutive therapy is not effective. Recent advances in genetics, epidemiology, biomarkers, pathophysiology, molecular mechanisms, and, in particular, the availability of treatments that may modify disease progression are opening new hopes in the care of these devastating disorders. MSA is a synucleinopathy with well characterized motor and autonomic dysfunction. MSA patients frequently show the presence of rapid eye movement (REM) behavior disorders, but the impact of neuropsychiatric disturbances and cognitive impairment in MSA needs further study. The availability of animal models and recent advances in the pathophysiology of α-synuclein accumulation are shedding light on the disease, opening new avenues for possible treatments.


Assuntos
Doenças dos Gânglios da Base/diagnóstico , Doenças dos Gânglios da Base/metabolismo , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/metabolismo , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/metabolismo , Doenças dos Gânglios da Base/terapia , Humanos , Atrofia de Múltiplos Sistemas/terapia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/terapia , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/terapia , Paralisia Supranuclear Progressiva/terapia , alfa-Sinucleína/antagonistas & inibidores , alfa-Sinucleína/metabolismo
13.
Clin Nucl Med ; 44(12): 987-988, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31524680

RESUMO

A 59-year-old man had developed within a few months walking disorders and rigidity of the left upper limb. I-FP-CIT SPECT/CT was performed in response to the suspicion of atypical parkinsonian syndrome. It showed an anomaly in presynaptic dopaminergic transmission on the right striatum and a voluminous expansive process on CT. MRI revealed an atypical meningioma. The patient had surgery for tumor removal. Later I-FP-CIT SPECT/CT showed normalization of presynaptic dopaminergic transmission on the right striatum.


Assuntos
Erros de Diagnóstico , Neoplasias Meníngeas/complicações , Neoplasias Meníngeas/diagnóstico , Meningioma/complicações , Meningioma/diagnóstico , Transtornos Parkinsonianos/complicações , Humanos , Imagem por Ressonância Magnética , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Neostriado/metabolismo , Transtornos Parkinsonianos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos
14.
Neuropeptides ; 78: 101971, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31540705

RESUMO

Alzheimer's and Parkinson's diseases are one of the world's leading causes of death. >50 million people throughout the world are suffering with these diseases. They are two distinct progressive neurodegenerative disorders affecting different regions of the brain with diverse symptoms, including memory and motor loss respectively, but with the advancement of diseases, both affect the whole brain and exhibit some common biological symptoms. For instance, >50% PD patients develop dementia in their later stages, though it is a hallmark of Alzheimer's disease. In fact, latest research has suggested the involvement of some common pathophysiological and genetic links between these diseases, including the deposition of pathological Aß, Tau, and α-synuclein in both the cases. Therefore, it is pertinent to diagnose the shared biomarkers, their aggregation mechanism, their intricate relationships in the pathophysiology of disease and therapeutic markers to target them. This would enable us to identify novel markers for the early detection of disease and targets for the future therapies. Herein, we investigated molecular aspects of Aß, Tau, and α-Synuclein aggregation, and characterized their functional partners involved in the pathology of AD and PD. Moreover, we identified the molecular-crosstalk between AD and PD associated with their pathogenic proteins- Aß, Tau, and α-Synuclein. Furthermore, we characterized their ubiquitinational enzymes and associated interaction network regulating the proteasomal clearance of these pathological proteins.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Bases de Dados de Proteínas , Humanos , Transtornos Parkinsonianos/metabolismo , Agregados Proteicos/fisiologia
15.
Exp Neurol ; 322: 113058, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31499061

RESUMO

Evidence indicates that depression is closely related to hyperactivity of the lateral habenula (LHb). However, it is not clear how activation and blockade of AMPA receptors (AMPARs) in the LHb affect depressive-like behaviors, particularly in Parkinson's disease-related depression. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced depressive-like behaviors and led to hyperactivity of LHb neurons compared to SNc sham-lesioned rats. Interestingly, intra-LHb injection of AMPAR agonist (S)-AMPA produced antidepressant-like effects in the two groups of rats and antagonist NBQX induced depressive-like behaviors, although (S)-AMPA excited LHb neurons and NBQX inhibited these neurons. We further found that intra-LHb injection of (S)-AMPA excited dopaminergic neurons in the anterior ventral tegmental area (aVTA) and serotonergic neurons in the dorsal raphe nucleus (DRN), which increased release of DA and 5-HT in the medial prefrontal cortex (mPFC), while NBQX induced the opposite effects. Further, lesioning the GABAergic rostromedial tegmental nucleus did not alter the proportions of the responses of these neurons to AMPAR stimulation. Additionally, lesions of the SNc reduced the level of p-GluR2-S880 in the LHb, which can increase the surface expression of calcium-impermeable GluR2-containing AMPARs (CI-AMPARs). This change in SNc-lesioned rats enhanced effects of (S)-AMPA and NBQX on the behaviors, LHb neuronal firing and release of DA and 5-HT. Collectively, antidepressant-like effects produced by (S)-AMPA attribute to activation of LHb neurons expressing CI-AMPAR, which excites aVTA dopaminergic neurons and DRN serotonergic neurons via the direct projection, thereby increasing release of mPFC DA and 5-HT.


Assuntos
Depressão/metabolismo , Habenula/metabolismo , Transtornos Parkinsonianos/metabolismo , Receptores de AMPA/metabolismo , Animais , Depressão/etiologia , Masculino , Transtornos Parkinsonianos/complicações , Ratos , Ratos Sprague-Dawley
16.
Neurotox Res ; 36(4): 700-711, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31367921

RESUMO

Prenatal and early life exposure of chlorpyrifos (CPF), a widely used pesticide, is known to cause neuronal deficits and Parkinson's disease (PD). However, data about the effect of its exposure at adult stages on PD-like symptoms and associated bone loss is scanty. In the present study, we investigated the impact of CPF on the behavioral alterations seen in PD using adult Swiss albino mice. PD is often associated with bone loss. Hence, skeletal changes were also evaluated using micro-computed tomography and histology. MPTP was used as a positive control. Cell culture studies using MC3T3E-1, SHSY5Y, and primary osteoclast cultures were done to understand the cellular mechanism for the behavioral and skeletal changes. Our results showed that CPF treatment leads to PD-like symptoms due to the loss of dopaminergic neurons. Moreover, CPF has a deleterious effect on the trabecular bone through both indirect changes in circulating factors and direct stimulation of multinucleate osteoclast cell formation. The impact on the bone mass was even stronger than MPTP. In conclusion, this is the first report demonstrating that CPF induces parkinsonian features in adult Swiss albino mice and it is accompanied by loss of trabecular bone.


Assuntos
Clorpirifos/toxicidade , Inseticidas/toxicidade , Osteoporose/induzido quimicamente , Osteoporose/patologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Acetilcolinesterase/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Masculino , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoporose/metabolismo , Transtornos Parkinsonianos/metabolismo
17.
Ann Neurol ; 86(4): 517-526, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31376168

RESUMO

OBJECTIVE: X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease with adult onset dystonia and subsequent parkinsonism. Postmortem and imaging studies revealed remarkable striatal pathology, with a predominant involvement of the striosomal compartment in the early phase. Here, we aimed to disentangle sequential neurodegeneration in the striatum of XDP patients, provide evidence for preferential loss of distinct striatal areas in the early phase, and investigate whether iron accumulation is present. METHODS: We used multimodal structural magnetic resonance imaging (voxel-based morphometry and relaxometry) in 18 male XDP patients carrying a TAF1 mutation and 19 age-matched male controls. RESULTS: Voxel-based relaxometry and morphometry revealed (1) a cluster in the anteromedial putamen showing high iron content and severe atrophy (-55%) and (2) a cluster with reduced relaxation rates as a marker for increased water levels and a lower degree of atrophy (-20%) in the dorsolateral putamen. Iron deposition correlated with the degree of atrophy (ρ = -0.585, p = 0.011) and disease duration (ρ = 0.632, p = 0.005) in the anteromedial putamen. In the dorsolateral putamen, sensorimotor putamen atrophy correlated with disease severity (ρ = -0.649, p = 0.004). INTERPRETATION: This multimodal approach identified a patchy pattern of atrophy within the putamen. Atrophy is advanced and associated with iron accumulation in rostral regions of the striatum, whereas neurodegeneration is moderate and still ongoing in dorsolateral areas. Given the short disease duration and predominant dystonic phenotype, these results are well in line with early and preferential degeneration of striosome-rich striatal areas in XDP. ANN NEUROL 2019;86:517-526.


Assuntos
Doenças dos Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/patologia , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/patologia , Degeneração Neural/patologia , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Adulto , Atrofia/patologia , Doenças dos Gânglios da Base/complicações , Doenças dos Gânglios da Base/metabolismo , Estudos de Casos e Controles , Distúrbios Distônicos/complicações , Humanos , Ferro/metabolismo , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/metabolismo , Putamen/diagnóstico por imagem , Putamen/metabolismo , Putamen/patologia , Índice de Gravidade de Doença , Adulto Jovem
18.
Mol Biol Rep ; 46(6): 5841-5858, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31396803

RESUMO

Parkinson's disease (PD) is a chronic neurodegenerative disease. Unfortunately, the effectiveness of anti-Parkinson treatments gradually diminishes owing to the progressive degeneration of the dopaminergic terminals. The research described here investigated the effect of adipose-derived mesenchymal stem cells (AD-MSC) versus that of an anti-Parkinson drug in a rat model of Parkinsonism. Forty adult rats were divided into four equal groups, each group receiving a different treatment: vehicle, rotenone, rotenone + AD-MSC, or rotenone + carbidopa/levodopa. Behavioral tests were carried out before and at the end of the treatment and specimens harvested from the midbrain were processed for light and electron microscopy. Genetic expression of glial fibrillary acidic protein (GFAP) and Nestin mRNA was assessed. Expression of the Lamin-B1 and Vimentin genes was measured, along with plasma levels of Angiopoietin-2 and dopamine. Treatment with rotenone induced pronounced motor deficits, as well as neuronal and glial alterations. The AD-MSC group showed improvements in motor function in the live animals and in the microscopic picture presented by their tissues. The fold change of both genes (GFAP and Nestin) decreased significantly in the AD-MSC and carbidopa/levodopa groups compared to the group with Parkinson's disease. Plasma levels of Angiopoietin-2 and dopamine were significantly increased after treatment (P < 0.001) compared to levels in the rats with Parkinson's disease. AD-MSC reduced neuronal degeneration more efficiently than did the anti-Parkinson drug in a rat model of Parkinsonism.


Assuntos
Tecido Adiposo/citologia , Transplante de Células-Tronco Mesenquimais , Transtornos Parkinsonianos , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/análise , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Células-Tronco Mesenquimais/citologia , Nestina/análise , Nestina/genética , Nestina/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/terapia , Ratos , Ratos Wistar , Substância Negra/química , Substância Negra/patologia , Transcriptoma
19.
IEEE Trans Nanobioscience ; 18(4): 535-541, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31398128

RESUMO

Silica nanoparticles (SiO2-NP) are an option as drug carriers due to their biodegradability, biocompatibility, and capacity to bind themselves to other compounds. However, until now, the effect of these particles on the brain when neurodegeneration occurs is unknown. Hence, this work focused on the in vivo evaluation of the neurotoxic effects of SiO2-NP when oxidative and inflammation are present during the development of Parkinson's disease. To determine whether SiO2-NP may act as a non-neurotoxic carrier we evaluated if the intragastric administration (ig) of SiO2-NP of 150 nm (25, 50 and 100 mg/kg administered for five consecutive days) increased neuronal damage induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. SiO2-NP administration did not further decrease cell viability assessed by MTT reduction, nor increased lipid peroxidation measured by TBARS or TNF α levels in the striatum and the substantia nigra in the MPTP model. Furthermore, we observed no additional reduction in striatal dopamine levels. The present results suggest that SiO2-NP of 150 nm are suitable nanocarrier for Parkinson's disease drugs without generating any additional damage.


Assuntos
Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Transtornos Parkinsonianos/tratamento farmacológico , Dióxido de Silício/administração & dosagem , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Transtornos Parkinsonianos/metabolismo , Serotonina/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Clin Neuropharmacol ; 42(5): 181-183, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31361666

RESUMO

OBJECTIVE: The objective of this study was to report long-lasting effects of bupropion on brain dopamine transporter (DAT) in a patient with depression and parkinsonism. METHODS: The patient was a 52-year old man who had been treated with 150 mg/d of bupropion for depression. The patient developed cognitive problems, bradykinesia, and reduced stride length for which he was scanned with [I]FP-CIT single photon emission computed tomography after the recommended 1-week discontinuation of bupropion. Levodopa treatment trial was initiated without a response. Eleven months later, the patient was scanned for a second time after a 1-month stoppage of bupropion. RESULTS: The first scan was abnormal with left putamen specific binding ratio of 1.99 (SDs from the reference value mean, -2.40), right putamen of 2.27 (SD, -1.84), left caudate of 2.33 (SD, -2.26), and right caudate of 2.29 (SD, -2.18). The second scan (after 1-month discontinuation) was normal, and specific binding ratios had increased from 5.2% to 31.7% in all striatal regions as compared with the first scan. Brain magnetic resonance imaging and [F]fluorodeoxyglucose positron emission tomography imaging were normal, and there was no levodopa response or other features supporting neurodegenerative parkinsonism. CONCLUSIONS: Bupropion has previously generally been discontinued 1 week prior DAT imaging, which meets the recommended, albeit arbitrary, time interval of 5 plasma clearance half-lives before the scan. One-week discontinuation of bupropion before DAT imaging may be insufficiently short. Our case shows that longer medication washout and rescan may be needed when there is contradiction between the imaging result and clinical outcome in patients with medications affecting DAT binding.


Assuntos
Bupropiona/efeitos adversos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Glucose/metabolismo , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/tratamento farmacológico , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA