Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.418
Filtrar
1.
Nat Commun ; 11(1): 5163, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057020

RESUMO

Parkinson's disease-associated kinase LRRK2 has been linked to IFN type II (IFN-γ) response in infections and to dopaminergic neuronal loss. However, whether and how LRRK2 synergizes with IFN-γ remains unclear. In this study, we employed dopaminergic neurons and microglia differentiated from patient-derived induced pluripotent stem cells carrying LRRK2 G2019S, the most common Parkinson's disease-associated mutation. We show that IFN-γ enhances the LRRK2 G2019S-dependent negative regulation of AKT phosphorylation and NFAT activation, thereby increasing neuronal vulnerability to immune challenge. Mechanistically, LRRK2 G2019S suppresses NFAT translocation via calcium signaling and possibly through microtubule reorganization. In microglia, LRRK2 modulates cytokine production and the glycolytic switch in response to IFN-γ in an NFAT-independent manner. Activated LRRK2 G2019S microglia cause neurite shortening, indicating that LRRK2-driven immunological changes can be neurotoxic. We propose that synergistic LRRK2/IFN-γ activation serves as a potential link between inflammation and neurodegeneration in Parkinson's disease.


Assuntos
Neurônios Dopaminérgicos/imunologia , Interferon gama/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Microglia/imunologia , Doença de Parkinson/imunologia , Sinalização do Cálcio/genética , Diferenciação Celular , Citocinas/metabolismo , Neurônios Dopaminérgicos/metabolismo , Técnicas de Inativação de Genes , Glicólise/genética , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Interferon gama/imunologia , Microscopia Intravital , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Microglia/metabolismo , Microtúbulos/metabolismo , Mutação , Fatores de Transcrição NFATC/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Cultura Primária de Células , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células THP-1
2.
Science ; 370(6512): 66-69, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004513

RESUMO

Dementia is a rapidly rising global health crisis that silently disables families and ends lives and livelihoods around the world. To date, however, no early biomarkers or effective therapies exist. It is now clear that brain microglia are more than mere bystanders or amyloid phagocytes; they can act as governors of neuronal function and homeostasis in the adult brain. Here, we highlight the fundamental role of microglia as tissue-resident macrophages in neuronal health. Then, we suggest how chronic impairment in microglia-neuron cross-talk may secure the permanence of the failure of synaptic and neuronal function and health in Alzheimer's and Parkinson's diseases. Understanding how to assess and modulate microglia-neuron interactions critical for brain health will be key to developing effective therapies for dementia.


Assuntos
Doença de Alzheimer/patologia , Amiloide/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Doença de Parkinson/patologia , Sinapses/patologia , Animais , Comunicação Celular , Humanos , Camundongos , Neurônios/metabolismo , Sinaptossomos/patologia , alfa-Sinucleína/metabolismo
3.
Int J Nanomedicine ; 15: 7615-7626, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116491

RESUMO

Purpose: Although single-walled nanotubes (SWNTs) with functional groups have been suggested as a potential nanomedicine to treat neuronal disorders, effective routes to administer SWNTs have not been compared thus far. The blood-brain barrier is a considerable challenge for the development of brain-targeting drugs, and therefore functionalized SWNT routes of administration have been needed for testing Parkinson's disease (PD) treatment. Here, effective administration routes of functionalized SWNTs were evaluated in PD mouse model. Methods: Three different administration routes were tested in PD mouse model. Functionalized SWNTs were injected directly into the lateral ventricle three days before (Method 1) or after (Method 2) 6-hydroxydopamine (6-OHDA) injection to compare the protective effects of SWNTs against dopaminergic neuronal death or functionalized SWNTs were injected intravenously at three and four days after 6-OHDA injection (Method 3). Asymmetric behaviors and histological assessment from all animals were performed at two weeks after 6-OHDA injection. Results: Ventricular injections of SWNTs both before or after 6-OHDA exposure protected dopaminergic neurons both in the substantia nigra and striatum and alleviated rotational asymmetry behavior in PD mice. Moreover, intravenous administration of SWNTs three and four days after 6-OHDA injection also prevented neuronal death and PD mice behavioral impairment without apparent cytotoxicity after six months post-treatment. Conclusion: Our study demonstrates that functionalized SWNTs could effectively protect dopaminergic neurons through all administration routes examined herein. Therefore, SWNTs are promising nanomedicine agents by themselves or as therapeutic carriers to treat neuronal disorders such as PD.


Assuntos
Neurônios Dopaminérgicos/patologia , Nanotubos de Carbono/química , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Administração Intravenosa , Animais , Antioxidantes/farmacologia , Comportamento Animal , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos ICR , Nanotubos de Carbono/ultraestrutura , Crescimento Neuronal/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Polietilenoglicóis/química , Tirosina 3-Mono-Oxigenase/metabolismo
4.
PLoS One ; 15(9): e0232808, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941428

RESUMO

Studies on evoked responses in Parkinson's disease (PD) may be useful for elucidating the etiology and quantitative evaluation of PD. However, in previous studies, the association between evoked responses and detailed motor symptoms or cognitive functions has not been clear. This study investigated the characteristics of the visual (VEF), auditory (AEF), and somatosensory (SEF) evoked magnetic fields in patients with Parkinson's disease (PD), and the correlations between evoked fields and the patient's clinical characteristics, motor symptoms, and cognitive functions. Twenty patients with PD and 10 healthy controls (HCs) were recruited as participants. We recorded VEF, AEF, and SEF, collected clinical characteristics, performed physical examinations, and administered 10 cognitive tests. We investigated differences in the latencies of the evoked fields between patients with PD and HCs. We also evaluated the correlation of the latencies with motor symptoms and cognitive functioning. There were significant differences between the two groups in 6 of the cognitive tests, all of which suggested mild cognitive impairment in patients with PD. The latencies of the VEF N75m, P100m, N145m, AEF P50m, P100m, and SEF P60m components were greater in the patients with PD than in the HCs. The latencies mainly correlated with medication and motor symptoms, less so with cognitive tests, with some elements of the correlations remaining significant after Bonferroni correction. In conclusion, the latencies of the VEF, AEF, and SEF were greater in PD patients than in HCs and were mainly correlated with medication and motor symptoms rather than cognitive functioning. Findings from this study suggest that evoked fields may reflect basal ganglia functioning and are candidates for assessing motor symptoms or the therapeutic effects of medication in patients with PD.


Assuntos
Potenciais Evocados , Campos Magnéticos , Doença de Parkinson/fisiopatologia , Idoso , Cognição , Feminino , Humanos , Magnetoencefalografia , Masculino , Pessoa de Meia-Idade , Movimento , Doença de Parkinson/patologia , Tempo de Reação
5.
Lancet Neurol ; 19(10): 872-878, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32949547

RESUMO

Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid ß after systemic injections of contaminated growth hormone extracts or dura mater grafts derived from cadavers. Even though these procedures are now obsolete, some reports raise the possibility of iatrogenic transmission of amyloid ß through putatively contaminated neurosurgical equipment. Iatrogenic transmission of amyloid ß might lead to amyloid deposition in the brain parenchyma and blood vessel walls, potentially resulting in cerebral amyloid angiopathy after several decades. Cerebral amyloid angiopathy can cause life-threatening brain haemorrhages; yet, there is no proof that the transmission of amyloid ß can also lead to Alzheimer's dementia. Large, long-term epidemiological studies and sensitive, cost-efficient tools to detect amyloid are needed to better understand any potential routes of amyloid ß transmission and to clarify whether other similar proteopathic seeds, such as tau or α-synuclein, can also be transferred iatrogenically.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Doenças Neurodegenerativas/metabolismo , Vigilância da População , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Animais , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patologia , Síndrome de Creutzfeldt-Jakob/transmissão , Humanos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fatores de Risco
6.
Ann Agric Environ Med ; 27(3): 326-334, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32955210

RESUMO

INTRODUCTION AND OBJECTIVE: αB-crystallin belongs to the ubiquitous family of small heat-shock proteins. It was discovered as a physiological protein of the eye lens, maintaining its liquid-like property. Furthermore, αB-crystallin was proved to playa bipolar role in both physiological and pathophysiological conditions. This review discusses current knowledge about the biology and genetics of αB-crystallin, and summarizes recent advances in understanding its role in ophthalmic and neurological disorders, as well as breast cancer, renal cancer and other malignancies. STATE OF KNOWLEDGE: α-crystallins are established as important elements of the protein quality control network, and consequently their defects are related to multiple human diseases. New studies highlight αB-crystallin's involvement in proliferative diabetic retinopathy angiogenesis and point out its therapeutic potential in age-related macular degeneration. αB-crystallin is thought to be associated with the disease-causing protein aggregates, leading to its connection with such neurological disturbances as anaplastic astrocytoma, Parkinson disease, aging deficits in the peripheral nervous system and multiple sclerosis. In breast cancer, it was proven to be a marker of aggressive behaviur and cerebral metastases. Strong expression of αB-crystallin promoted growth and migration of clear cell renal cell carcinoma cells and was correlated with lower overall survival rate. Considering other malignancies, its various roles were established in colorectal and gastric cancers, head and neck squamous cell carcinomas and osteosarcomas. CONCLUSIONS: Further studies concerning αB-crystallin seem to be enormously promising, as they might improve our understanding of common human pathologies as well as contemporary diagnostics and treatment.


Assuntos
Astrocitoma/patologia , Neoplasias da Mama/patologia , Cristalinas/metabolismo , Retinopatia Diabética/patologia , Esclerose Múltipla/patologia , Doenças do Sistema Nervoso/patologia , Doença de Parkinson/patologia , Feminino , Humanos , Sistema Nervoso Periférico/patologia
7.
J Vis Exp ; (162)2020 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-32865527

RESUMO

The goal of this protocol is to establish a robust and reproducible model of α-synuclein accumulation in primary dopamine neurons. Combined with immunostaining and unbiased automated image analysis, this model allows for the analysis of the effects of drugs and genetic manipulations on α-synuclein aggregation in neuronal cultures. Primary midbrain cultures provide a reliable source of bona fide embryonic dopamine neurons. In this protocol, the hallmark histopathology of Parkinson's disease, Lewy bodies (LB), is mimicked by the addition of α-synuclein pre-formed fibrils (PFFs) directly to neuronal culture media. Accumulation of endogenous phosphorylated α-synuclein in the soma of dopamine neurons is detected by immunostaining already at 7 days after the PFF addition. In vitro cell culture conditions are also suitable for the application and evaluation of treatments preventing α-synuclein accumulation, such as small molecule drugs and neurotrophic factors, as well as lentivirus vectors for genetic manipulation (e.g., with CRISPR/Cas9). Culturing the neurons in 96 well plates increases the robustness and power of the experimental setups. At the end of the experiment, the cells are fixed with paraformaldehyde for immunocytochemistry and fluorescence microscopy imaging. Multispectral fluorescence images are obtained via automated microscopy of 96 well plates. These data are quantified (e.g., counting the number of phospho-α-synuclein-containing dopamine neurons per well) with the use of free software that provides a platform for unbiased high-content phenotype analysis. PFF-induced modeling of phosphorylated α-synuclein accumulation in primary dopamine neurons provides a reliable tool to study the underlying mechanisms mediating formation and elimination of α-synuclein inclusions, with the opportunity for high-throughput drug screening and cellular phenotype analysis.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Embrião de Mamíferos/citologia , Mesencéfalo/citologia , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Animais , Citoesqueleto/metabolismo , Mesencéfalo/patologia , Camundongos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Agregados Proteicos
8.
PLoS One ; 15(8): e0236820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756578

RESUMO

Dance may help individuals living with Parkinson's disease (PD) improve motor and non-motor symptoms that impact quality of life (QOL). The primary aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the efficacy of dance in improving motor and non-motor symptoms of PD and QOL. The secondary aims of this review were to evaluate the methodological quality of included studies by assessing risk of bias across nine categories and to inform the direction of future research. Peer-reviewed RCTs that included people living with PD at all disease stages and ages and measured the effects of a dance intervention longer than one day were included. Sixteen RCTs involving 636 participants with mild to moderate PD were eligible for inclusion in the qualitative synthesis and nine in the meta-analysis. Overall, the reviewed evidence demonstrated that dance can improve motor impairments, specifically balance and motor symptom severity in individuals with mild to moderate PD, and that more research is needed to determine its effects on non-motor symptoms and QOL. RCTs that use a mixed-methods approach and include larger sample sizes will be beneficial in fully characterizing effects and in determining which program elements are most important in bringing about positive, clinically meaningful changes in people with PD.


Assuntos
Dança , Transtornos Motores/complicações , Doença de Parkinson/patologia , Qualidade de Vida , Atividades Cotidianas , Cognição/fisiologia , Marcha , Humanos , Saúde Mental , Doença de Parkinson/complicações , Equilíbrio Postural
9.
PLoS One ; 15(8): e0236886, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790749

RESUMO

Falls pose a serious problem in elderly and clinical populations. Most often, they lead to a loss of mobility and independence. They might also be an indirect cause of death. The aim of this study was to determine an objective predictor of the fear of falling and falls in elderly subjects (ESs) and Parkinson's disease (PD) subjects. Thirty-two ESs were examined in this study, of whom sixteen were diagnosed with PD. The testing procedures comprised force plate measurements (limit of stability test-LOS test) and clinical tests (Berg Balance Scale, Functional Reach Test, Timed Up and Go test, Tinetti test). The Falls Efficacy Scale International (FES-I) was used to evaluate the fear of falling. The range of the maximum forward lean was normalized to the length from the ankle joint to the head of the first metatarsal bone and was named the functional forward stability indicator (FFSI). The FFSI, derived from the LOS test, allowed us to demonstrate the real deficit in functional stability and individual safety margins. Moreover, the FFSI was highly correlated with the FES-I score and almost all clinical test results in elderly subjects (r>0,6; p<0.05). In PD subjects, the FFSI was poorly correlated with the fear of falling, the BBS score and the FR distance; however, a high correlation with the Tinetii test (r>0,6, p<0.05) was noted. The PD subjects presented a different balance strategy when close to their stability limits, which was also reflected in the lower values of sample entropy (t = (-2.40); p<0.05; d = 0.87). The FFSI might be a good predictor of the fear of falling in the group of elderly people. Additionally, the FFSI allows us to show real balance deficits both in PD subjects and in their healthy peers without the need for a reference group and norms. In conclusion, it is postulated that the popular clinical assessments of postural balance in PD subjects should be accompanied by reliable posturography measurements.


Assuntos
Acidentes por Quedas/estatística & dados numéricos , Doença de Parkinson/diagnóstico , Idoso , Antropometria , Entropia , Medo/psicologia , Feminino , Idoso Fragilizado , Humanos , Masculino , Doença de Parkinson/patologia , Equilíbrio Postural , Índice de Gravidade de Doença
10.
PLoS One ; 15(8): e0237472, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817705

RESUMO

A higher levodopa dose is a strong risk factor for levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD). However, levodopa dose can change during long-term medication. We explored the relationship between levodopa dose and time to onset of LID using longitudinal multicenter data. Medical records of 150 patients who were diagnosed with de novo PD and treated with levodopa until onset of LID were collected. Levodopa dose were assessed as the dose at 6 months from levodopa initiation and rate of dose increase between 6 months and onset of LID. The groups with earlier LID onset had higher levodopa and levodopa-equivalent dose at the first 6 months of treatment and rapid increase in both levodopa and levodopa-equivalent dose. Multivariable linear regression models revealed that female sex, severe motor symptom at levodopa initiation, and higher rate of increase in both levodopa and levodopa-equivalent dose were significantly associated with early onset of LID. The present results demonstrated that rapid increase in levodopa dose or levodopa-equivalent dose is associated with early onset of LID.


Assuntos
Antiparkinsonianos/uso terapêutico , Discinesia Induzida por Medicamentos/diagnóstico , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Idoso , Antiparkinsonianos/efeitos adversos , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/etiologia , Feminino , Humanos , Levodopa/uso terapêutico , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/patologia , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais
11.
PLoS One ; 15(8): e0237498, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822437

RESUMO

The EARLYSTIM Study compared deep brain stimulation (DBS) with best medical treatment (BMT) over 2-years, showing a between-group difference of 8.0 from baseline in favor of DBS in health-related quality of life (HRQoL), measured with the PDQ-39 SI (summary index). This study obtained complementary information about the importance of the change in HRQoL as measured by the PDQ-39, using anchor-based (Patient Global Impression of Change, PGIC) and distribution-based techniques (magnitude of change, effect size, thresholds, distribution of benefit) applied to the EARLYSTIM study data. Anchor-based techniques showed a difference follow-up-baseline for patients who reported "minimal improvement" of -5.8 [-9.9, -1.6] (mean [95%CI]) in the DBS group vs -2.9 [-9.0, 3.1] in the BMT group. As the vast majority (80.8%) of DBS patients reported "much or very much improvement", this difference was explored for the latter group and amounted to -8.7 for the DBS group and -6.5 in the BMT group. Distribution-based techniques that analyzed the relative change and treatment effect size showed a moderate benefit of the DBS on the HRQoL, whereas a slight worsening was observed in the BMT group. The change in the DBS group (-7.8) was higher than the MIC (Minimally Important Change) estimated value (-5.8 by the anchor; -6.3 by triangulation of thresholds), but not in the BMT (0.2 vs. -3.0 to -5.4, respectively). Almost 90% of the patients in the DBS group declared some improvement (58.3% and 56.7% beyond the estimated MIC), which was significantly different from the BMT group whose proportions were 32.0% and 30.3%, respectively. The number needed to treat to improve ≥1 MIC by DBS vs BMT was 3.8. Change in depression, disability and pain influenced the improvement of the DBS group. DBS improved HRQoL in a high proportion of patients to a significant and moderate degree, at 2 years follow-up.


Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson/terapia , Qualidade de Vida , Atividades Cotidianas , Estudos de Coortes , Humanos , Levodopa/uso terapêutico , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Doença de Parkinson/psicologia , Índice de Gravidade de Doença , Resultado do Tratamento
13.
J Pharmacol Sci ; 144(3): 183-187, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32807663

RESUMO

Oxidative stress is associated with the progression of the neurodegenerative diseases Parkinson's disease (PD) and cerebral ischemia. Recently, 5-aminolevulinic acid (5-ALA), an intermediate in the porphyrin synthesis pathway, was reported to exert antioxidative effects on macrophages and cardiomyocytes. Here, we demonstrated the neuroprotective effects of 5-ALA using rat models of PD and ischemia as well as in vitro in SH-SY5Y cells. 5-ALA partially prevented neurodegeneration in each condition. These results suggest that 5-ALA has a potential for promising therapeutic agent to protect against neurodegeneration exacerbated by oxidative stress.


Assuntos
Isquemia Encefálica/patologia , Ácidos Levulínicos/farmacologia , Degeneração Neural , Fármacos Neuroprotetores , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/patologia , Acidente Vascular Cerebral/patologia , Animais , Isquemia Encefálica/etiologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Ácidos Levulínicos/uso terapêutico , Masculino , Degeneração Neural/prevenção & controle , Doença de Parkinson/etiologia , Ratos Wistar , Acidente Vascular Cerebral/etiologia
14.
Proc Natl Acad Sci U S A ; 117(29): 17296-17307, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32631998

RESUMO

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of late-onset, autosomal-dominant familial Parkinson's disease (PD). LRRK2 functions as both a kinase and GTPase, and PD-linked mutations are known to influence both enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage in culture models, the mechanisms underlying these pathogenic effects remain uncertain. Rodent models containing familial LRRK2 mutations often lack robust PD-like neurodegenerative phenotypes. Here, we develop a robust preclinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or administration of the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the robust destabilization of human LRRK2 protein in the brain relative to endogenous LRRK2. Our study further demonstrates that G2019S LRRK2-induced dopaminergic neurodegeneration critically requires normal GTPase activity, as hypothesis-testing mutations that increase GTP hydrolysis or impair GTP-binding activity provide neuroprotection although via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent preclinical model of LRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.


Assuntos
Neurônios Dopaminérgicos/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Doença de Parkinson/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular , Modelos Animais de Doenças , Dopamina/metabolismo , Feminino , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Camundongos , Camundongos Knockout , Mutação , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/patologia , Fenótipo , Projetos Piloto , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Wistar , Substância Negra
15.
Anticancer Res ; 40(6): 3169-3190, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487612

RESUMO

BACKGROUND/AIM: During the last two decades, Parkinson's disease (PD)-associated genes have been associated with cancer; however, a shared pathogenic mechanism has yet to be discovered. Parkin, an E3 ubiquitin ligase that is involved in early-onset Parkinson's disease, has also been reported to exert tumor suppressor activity. However, the details about the role of Parkin in cancer remain unknown. The present study aimed at identifying differentially regulated nuclear proteins and nuclear phosphoproteins whose levels were affected by Parkin expression. MATERIALS AND METHODS: SHS-SY5Y cells expressing either wild-type Parkin or its mutant under tetracycline control were used in this study; cells not expressing Parkin served as control. Nuclear proteins were enriched from Parkin-expressing and control cells to perform a comparative proteomics study using two-dimensional gel electrophoresis (2D) coupled to matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF/TOF) mass spectrometry analysis. Changes in phosphoproteome and nuclear phosphoproteome were also studied by staining the 2D gels with ProQ diamond phosphoprotein stain. The identified proteins were subjected to bioinformatics analysis to elucidate the reactomes and relevant pathways. RESULTS: Six nuclear proteins, namely NCL, DDIT3, PARP1, HMGB1, TCTP and TPI were shown to be differentially regulated in cells expressing Parkin protein. Regulations in phosphorylation levels of ENPL, PRDX4, ECHM, ALDOA SET, DHSA, RCC1 and DULRD were also detected. Bioinformatics analysis of differentially regulated proteins highlighted the involvement of Parkin in DNA repair. CONCLUSION: Several nuclear protein candidates whose expression or phosphorylation levels were altered in cells expressing Parkin. Bioinformatics analysis of these proteins indicated that the nuclear form of Parkin may play a significant role in DNA repair and contribute to prevention of tumorogenesis via maintaining DNA integrity.


Assuntos
Doença de Parkinson/genética , Proteoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular Tumoral , Humanos , Doença de Parkinson/patologia
16.
PLoS One ; 15(6): e0234519, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530970

RESUMO

Axonal damage leads to the release of neurofilament light chain (NFL), which enters the CSF or blood. In this work, an assay kit for plasma NFL utilizing immunomagnetic reduction (IMR) was developed. Antibodies against NFL were immobilized on magnetic nanoparticles to develop an IMR NFL kit. The preclinical properties, such as the standard curve, limit of detection (LoD), and dynamic range, were characterized. Thirty-one normal controls (NC), fifty-two patients with Parkinson's disease (PD) or PD dementia (PDD) and thirty-one patients with Alzheimer's disease (AD) were enrolled in the study evaluating the plasma NFL assay using an IMR kit. T-tests and receiver operating characteristic (ROC) curve analysis were performed to investigate the capability for discrimination among the clinical groups according to plasma NFL levels. The LoD of the NFL assay using the IMR kit was found to be 0.18 fg/ml. The dynamic range of the NFL assay reached 1000 pg/ml. The NC group showed a plasma NFL level of 7.70 ± 4.00 pg/ml, which is significantly lower than that of the PD/PDD (15.85 ± 7.82 pg/ml, p < 0.001) and AD (19.24 ± 8.99 pg/ml, p < 0.001) groups. A significant difference in plasma NFL levels was determined between the PD and AD groups (p < 0.01). Through ROC curve analysis, the cut-off value of the plasma NFL concentration for differentiating NCs from dementia patients (AD and PD/PDD) was found to be 12.71 pg/ml, with a clinical sensitivity and specificity of 73.5% and 90.3%, respectively. The AUC was 0.868. Furthermore, the cut-off value of the plasma NFL concentration for discriminating AD from PD/PDD was found to be 18.02 pg/ml, with a clinical sensitivity and specificity of 61.3% and 65.4%, respectively. The AUC was 0.630. An ultrasensitive assay for measuring plasma NFL utilizing IMR technology was developed. Clear differences in plasma NFL concentrations were observed among NCs and PD and AD patients. These results imply that the determination of plasma NFL is promising not only for screening dementia but also for differential diagnosis.


Assuntos
Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Proteínas de Neurofilamentos/sangue , Proteínas tau/sangue , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Axônios/metabolismo , Axônios/patologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Feminino , Humanos , Separação Imunomagnética , Filamentos Intermediários/genética , Filamentos Intermediários/patologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/sangue , Doença de Parkinson/genética , Doença de Parkinson/patologia
17.
PLoS Genet ; 16(6): e1008868, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32579581

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder featuring progressive loss of midbrain dopaminergic (DA) neurons that leads to motor symptoms. The etiology and pathogenesis of PD are not clear. We found that expression of COUP-TFII, an orphan nuclear receptor, in DA neurons is upregulated in PD patients through the analysis of public datasets. We show here that through epigenetic regulation, COUP-TFII contributes to oxidative stress, suggesting that COUP-TFII may play a role in PD pathogenesis. Elevated COUP-TFII expression specifically in DA neurons evokes DA neuronal loss in mice and accelerates the progression of phenotypes in a PD mouse model, MitoPark. Compared to control mice, those with elevated COUP-TFII expression displayed reduced cristae in mitochondria and enhanced cellular electron-dense vacuoles in the substantia nigra pars compacta. Mechanistically, we found that overexpression of COUP-TFII disturbs mitochondrial pathways, resulting in mitochondrial dysfunction. In particular, there is repressed expression of genes encoding cytosolic aldehyde dehydrogenases, which could enhance oxidative stress and interfere with mitochondrial function via 3,4-dihydroxyphenylacetaldehyde (DOPAL) buildup in DA neurons. Importantly, under-expression of COUP-TFII in DA neurons slowed the deterioration in motor functions of MitoPark mice. Taken together, our results suggest that COUP-TFII may be an important contributor to PD development and a potential therapeutic target.


Assuntos
Fator II de Transcrição COUP/metabolismo , Neurônios Dopaminérgicos/patologia , Mitocôndrias/patologia , Doença de Parkinson/genética , Ácido 3,4-Di-Hidroxifenilacético/análogos & derivados , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Aldeído Desidrogenase , Animais , Encéfalo/citologia , Encéfalo/patologia , Linhagem Celular , Linhagem Celular Tumoral , Estudos de Coortes , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Progressão da Doença , Neurônios Dopaminérgicos/citologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Estresse Oxidativo/genética , Doença de Parkinson/patologia , Cultura Primária de Células , RNA-Seq , Ratos , Regulação para Cima
19.
Exp Mol Pathol ; 115: 104478, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32511947

RESUMO

OBJECTIVES: Astragaloside-IV (AS-IV) protects the nerve cells of Parkinson's disease (PD) from damage. Long non-coding RNA (lincRNA) has been found to be important for many diseases. Lincnra-p21 is abnormally expressed in PD. The purpose of this study was to investigate whether Astragaloside-IV (AS-IV) affects endoplasmic reticulum stress (ERS)-induced neuronal apoptosis in PD, and its possible mechanisms. METHODS: The PD mouse model was established via injecting 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP) and the PD cell model was established via inducing the MN9D cell line with 1-methyl-4-pehnyl-pyridine (MPP+). The behavioral testing of PD model mice was tested after AS-IV treatment and PD-related lincRNAs expression were detected by qRT-PCR. After treatment of PD model cells with AS-IV, lincRNA-p21 expression was detected by qRT-PCR, and cell viability and apoptosis were detected by MTT assay and flow cytometry, respectively. The binding of lincRNA-p21 to C/EBP-homologous (CHOP) protein was investigated by RNA immunoprecipitation and RNA pull-down, and the effect of lincRNA-p21 on the ubiquitination of CHOP protein was examined by ubiquitination assay. The role of lincRNA-p21 in PD model was studied by cell transfection. RESULTS: In PD mice, AS-IV can improve the behavior of mice and significantly inhibit expression of lincRNA-p21. Similarly, AS-IV can obviously restrain the expression of lincRNA-p21 in PD cells, and obviously elevated cell viability and restrained apoptosis. LincRNA-p21 is able to bind to CHOP protein. Further studies showed that restraint of lincRNA-p21 expression can facilitate ubiquitination of CHOP and accelerate its protein degradation. In AS-IV-treated PD model cells, overexpression of lincRNA-p21 lessened cell viability and facilitated apoptosis, whereas low expression of CHOP reversed this result. CONCLUSION: In this study, we found that AS-IV can lessen the expression of CHOP protein by restraining the expression of lincRNA-p21 in the PD model, thereby inhibiting neuronal apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neurônios/patologia , Doença de Parkinson/patologia , RNA Longo não Codificante/metabolismo , Saponinas/farmacologia , Fator de Transcrição CHOP/metabolismo , Triterpenos/farmacologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Estabilidade Proteica , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos
20.
NeuroRehabilitation ; 46(4): 529-537, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32538880

RESUMO

BACKGROUND: Pisa syndrome (PS) is a clinical condition frequently associated with Parkinson's disease (PD). It is characterized by a trunk lateral flexion higher than 10 degrees and reversible when lying. One pathophysiological hypothesis is the altered verticality perception, due to a somatosensory impairment. Osteopathic Manipulative Treatment (OMT) manages fascial-system alterations, linked to somatic dysfunctions. Fascial system showed to be implicated in proprioceptive sensibility. OBJECTIVE: The aim of the study was to assess OMT efficacy on postural control in PD-PS patients by stabilometry. METHODS: In this single-blinded trial we studied 24 PD-PS patients, 12 of whom were randomly assigned to receive a multidisciplinary physical therapy protocol (MIRT) and sham OMT, while the other 12 received four OMT plus MIRT, for one month. The primary endpoint was the eye closed sway area assessment after the intervention. Evaluation of trunk lateral flexion (TLF) with DIERS formetrics was also performed. RESULTS: At one month, the sway area of the OMT group significantly decreased compared to placebo (mean delta OMT - 326.00±491.24 mm2, p = 0.01). In the experimental group TLF showed a mean inclination reduction of 3.33 degrees after treatment (p = 0.044, mean d = 0.54). Moreover, a significant positive association between delta ECSA and delta TLF was observed (p = 0.04, r = 0.46). DISCUSSION: Among PD-PS patients, MIRT plus OMT showed preliminary evidence of postural control and TLF improvement, compared to the control group.


Assuntos
Manipulação Osteopática/métodos , Doença de Parkinson/terapia , Equilíbrio Postural , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/patologia , Postura
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA