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1.
EMBO J ; 41(2): e105531, 2022 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34904718

RESUMO

Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3C57Y has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.


Assuntos
Deficiências do Desenvolvimento/genética , Retículo Endoplasmático/metabolismo , Isomerases de Dissulfetos de Proteínas/genética , Proteostase , Adolescente , Adulto , Animais , Axônios/metabolismo , Axônios/patologia , Adesão Celular , Células Cultivadas , Criança , Citoesqueleto/metabolismo , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Integrinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Crescimento Neuronal , Plasticidade Neuronal , Linhagem , Isomerases de Dissulfetos de Proteínas/metabolismo , Peixe-Zebra
2.
J Biol Chem ; 298(7): 102087, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35654139

RESUMO

Protein disulfide isomerases (PDIs) constitute a family of oxidoreductases promoting redox protein folding and quality control in the endoplasmic reticulum. PDIs catalyze disulfide bond formation, isomerization, and reduction, operating in concert with molecular chaperones to fold secretory cargoes in addition to directing misfolded proteins to be refolded or degraded. Importantly, PDIs are emerging as key components of the proteostasis network, integrating protein folding status with central surveillance mechanisms to balance proteome stability according to cellular needs. Recent advances in the field driven by the generation of new mouse models, human genetic studies, and omics methodologies, in addition to interventions using small molecules and gene therapy, have revealed the significance of PDIs to the physiology of the nervous system. PDIs are also implicated in diverse pathologies, ranging from neurodevelopmental conditions to neurodegenerative diseases and traumatic injuries. Here, we review the principles of redox protein folding in the ER with a focus on current evidence linking genetic mutations and biochemical alterations to PDIs in the etiology of neurological conditions.


Assuntos
Retículo Endoplasmático , Sistema Nervoso , Isomerases de Dissulfetos de Proteínas , Proteostase , Animais , Retículo Endoplasmático/metabolismo , Humanos , Camundongos , Sistema Nervoso/metabolismo , Doenças Neurodegenerativas , Oxirredução , Isomerases de Dissulfetos de Proteínas/metabolismo , Dobramento de Proteína
3.
Nurs Crit Care ; 28(6): 1143-1153, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37621180

RESUMO

BACKGROUND: Trauma is the most common cause of death and disability in the paediatric population. There are a huge number of variables involved in the care they receive from health care professionals. AIM: The aim of this study was to review the available evidence of initial paediatric trauma care throughout the health care process with a view to create quality indicators (QIs). STUDY DESIGN: A systematic review was performed from Cochrane Library, Medline, Scopus and SciELO between 2010 and 2020. Studies and guidelines that examined quality or suggested QI were included. Indicators were classified by health care setting, Donabedian's model, risk of bias and the quality of the publication with the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment. RESULTS: The initial search included 686 articles, which were reduced to 22, with 15 primary and 7 secondary research articles. The snowball sampling technique was used to add a further seven guidelines and two articles. From these, 534 possible indicators were extracted, summarizing them into 39 and grouping the prehospital care indicators as structure (N = 5), process (N = 12) and outcome (N = 3) indicators and the hospital care indicators as structure (N = 4), process (N = 10) and outcome (N = 6) indicators. Most of the QIs have been extracted from US studies. They are multidisciplinary and in some cases are based on an adaptation of the QIs of adult trauma care. CONCLUSIONS: There was a clear gap and large variability between the indicators, as well as low-quality evidence. Future studies will validate indicators using the Delphi method. RELEVANCE TO CLINICAL PRACTICE: Design a QI framework that may be used by the health system throughout the process. Indicators framework will get nurses, to assess the quality of health care, detect deficient areas and implement improvement measures.


Assuntos
Serviços Médicos de Emergência , Indicadores de Qualidade em Assistência à Saúde , Adulto , Humanos , Criança , Atenção à Saúde , Unidades de Terapia Intensiva Pediátrica
4.
Biol Res ; 55(1): 31, 2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36266673

RESUMO

Genetic modification of living organisms has been a prosperous activity for research and development of agricultural, industrial and biomedical applications. Three decades have passed since the first genetically modified products, obtained by transgenesis, become available to the market. The regulatory frameworks across the world have not been able to keep up to date with new technologies, monitoring and safety concerns. New genome editing techniques are opening new avenues to genetic modification development and uses, putting pressure on these frameworks. Here we discuss the implications of definitions of living/genetically modified organisms, the evolving genome editing tools to obtain them and how the regulatory frameworks around the world have taken these technologies into account, with a focus on agricultural crops. Finally, we expand this review beyond commercial crops to address living modified organism uses in food industry, biomedical applications and climate change-oriented solutions.


Assuntos
Produtos Agrícolas , Edição de Genes , Edição de Genes/métodos , Plantas Geneticamente Modificadas/genética , Produtos Agrícolas/genética , Biotecnologia , Agricultura , Genoma de Planta
5.
Proc Natl Acad Sci U S A ; 115(32): 8209-8214, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30038021

RESUMO

Abnormal modifications to mutant superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS). Misfolding of wild-type SOD1 (SOD1WT) is also observed in postmortem tissue of a subset of sporadic ALS (sALS) cases, but cellular and molecular mechanisms generating abnormal SOD1WT species are unknown. We analyzed aberrant human SOD1WT species over the lifetime of transgenic mice and found the accumulation of disulfide-cross-linked high-molecular-weight SOD1WT aggregates during aging. Subcellular fractionation of spinal cord tissue and protein overexpression in NSC-34 motoneuron-like cells revealed that endoplasmic reticulum (ER) localization favors oxidation and disulfide-dependent aggregation of SOD1WT We established a pharmacological paradigm of chronic ER stress in vivo, which recapitulated SOD1WTaggregation in young transgenic mice. These species were soluble in nondenaturing detergents and did not react with a SOD1 conformation-specific antibody. Interestingly, SOD1WT aggregation under ER stress correlated with astrocyte activation in the spinal cord of transgenic mice. Finally, the disulfide-cross-linked SOD1WT species were also found augmented in spinal cord tissue of sALS patients, correlating with the presence of ER stress markers. Overall, this study suggests that ER stress increases the susceptibility of SOD1WT to aggregate during aging, operating as a possible risk factor for developing ALS.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Estresse do Retículo Endoplasmático/fisiologia , Medula Espinal/patologia , Superóxido Dismutase-1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Esclerose Lateral Amiotrófica/genética , Animais , Astrócitos/patologia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Neurônios Motores , Mutação , Oxirredução , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , Dobramento de Proteína , Proteostase/fisiologia , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Superóxido Dismutase-1/genética , Triptofano/metabolismo , Tunicamicina/farmacologia , Resposta a Proteínas não Dobradas/fisiologia
6.
EMBO J ; 35(8): 845-65, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26869642

RESUMO

Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized fourALS-linked mutations recently identified in two majorPDIgenes,PDIA1 andPDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of thesePDIvariants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutantPDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of thesePDImutants. Finally, targetingERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifiesERproteostasis imbalance as a risk factor forALS, driving initial stages of the disease.


Assuntos
Esclerose Lateral Amiotrófica/genética , Neurônios Motores/patologia , Pró-Colágeno-Prolina Dioxigenase/genética , Isomerases de Dissulfetos de Proteínas/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Animais Geneticamente Modificados , Eletromiografia , Embrião não Mamífero , Estresse do Retículo Endoplasmático/genética , Humanos , Camundongos Knockout , Mutação , Neuritos/patologia , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética
7.
J Biol Chem ; 290(39): 23631-45, 2015 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-26170458

RESUMO

Although the accumulation of a misfolded and protease-resistant form of the prion protein (PrP) is a key event in prion pathogenesis, the cellular factors involved in its folding and quality control are poorly understood. PrP is a glycosylated and disulfide-bonded protein synthesized at the endoplasmic reticulum (ER). The ER foldase ERp57 (also known as Grp58) is highly expressed in the brain of sporadic and infectious forms of prion-related disorders. ERp57 is a disulfide isomerase involved in the folding of a subset of glycoproteins in the ER as part of the calnexin/calreticulin cycle. Here, we show that levels of ERp57 increase mainly in neurons of Creutzfeldt-Jacob patients. Using gain- and loss-of-function approaches in cell culture, we demonstrate that ERp57 expression controls the maturation and total levels of wild-type PrP and mutant forms associated with human disease. In addition, we found that PrP physically interacts with ERp57, and also with the closest family member PDIA1, but not ERp72. Furthermore, we generated a conditional knock-out mouse for ERp57 in the nervous system and detected a reduction in the steady-state levels of the mono- and nonglycosylated forms of PrP in the brain. In contrast, ERp57 transgenic mice showed increased levels of endogenous PrP. Unexpectedly, ERp57 expression did not affect the susceptibility of cells to ER stress in vitro and in vivo. This study identifies ERp57 as a new modulator of PrP levels and may help with understanding the consequences of ERp57 up-regulation observed in human disease.


Assuntos
Príons/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Animais , Linhagem Celular , Síndrome de Creutzfeldt-Jakob/metabolismo , Humanos , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Dobramento de Proteína
8.
Acta Neuropathol Commun ; 9(1): 21, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33541434

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease that affects motoneurons. Mutations in superoxide dismutase 1 (SOD1) have been described as a causative genetic factor for ALS. Mice overexpressing ALS-linked mutant SOD1 develop ALS symptoms accompanied by histopathological alterations and protein aggregation. The protein disulfide isomerase family member ERp57 is one of the main up-regulated proteins in tissue of ALS patients and mutant SOD1 mice, whereas point mutations in ERp57 were described as possible risk factors to develop the disease. ERp57 catalyzes disulfide bond formation and isomerization in the endoplasmic reticulum (ER), constituting a central component of protein quality control mechanisms. However, the actual contribution of ERp57 to ALS pathogenesis remained to be defined. Here, we studied the consequences of overexpressing ERp57 in experimental ALS using mutant SOD1 mice. Double transgenic SOD1G93A/ERp57WT animals presented delayed deterioration of electrophysiological activity and maintained muscle innervation compared to single transgenic SOD1G93A littermates at early-symptomatic stage, along with improved motor performance without affecting survival. The overexpression of ERp57 reduced mutant SOD1 aggregation, but only at disease end-stage, dissociating its role as an anti-aggregation factor from the protection of neuromuscular junctions. Instead, proteomic analysis revealed that the neuroprotective effects of ERp57 overexpression correlated with increased levels of synaptic and actin cytoskeleton proteins in the spinal cord. Taken together, our results suggest that ERp57 operates as a disease modifier at early stages by maintaining motoneuron connectivity.


Assuntos
Esclerose Lateral Amiotrófica/enzimologia , Esclerose Lateral Amiotrófica/prevenção & controle , Isomerases de Dissulfetos de Proteínas/genética , Isomerases de Dissulfetos de Proteínas/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Modelos Animais de Doenças , Eletromiografia , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Denervação Muscular , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Junção Neuromuscular/metabolismo , Proteômica , Medula Espinal/patologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo
9.
Biol. Res ; 55: 31-31, 2022. ilus, tab, graf
Artigo em Inglês | LILACS | ID: biblio-1403566

RESUMO

Genetic modification of living organisms has been a prosperous activity for research and development of agricultural, industrial and biomedical applications. Three decades have passed since the first genetically modified products, obtained by transgenesis, become available to the market. The regulatory frameworks across the world have not been able to keep up to date with new technologies, monitoring and safety concerns. New genome editing techniques are opening new avenues to genetic modification development and uses, putting pressure on these frameworks. Here we discuss the implications of definitions of living/genetically modified organisms, the evolving genome editing tools to obtain them and how the regulatory frameworks around the world have taken these technologies into account, with a focus on agricultural crops. Finally, we expand this review beyond commercial crops to address living modified organism uses in food industry, biomedical applications and climate change-oriented solutions.


Assuntos
Produtos Agrícolas/genética , Edição de Genes/métodos , Biotecnologia , Plantas Geneticamente Modificadas/genética , Genoma de Planta , Agricultura
10.
Neurosci Lett ; 636: 9-15, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27150076

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease characterized by the selective loss of motoneurons. The mechanisms underlying neuronal degeneration in ALS are starting to be elucidated, highlighting abnormal protein aggregation and altered mRNA metabolism as common phenomena. ALS involves the selective vulnerablility of a subpopulation of motoneurons, suggesting that intrinsic factors may determine ALS pathogenesis. Accumulating evidence indicates that alterations to endoplasmic reticulum (ER) proteostasis play a critical role on disease progression, representing one of the earliests pathological signatures of the disease. Here we discuss recent studies uncovering a fundamental role of ER stress as the driver of selective neuronal vulnerability in ALS and discuss the potential of targeting the unfolded protein response (UPR) as a therapeutic strategy to treat ALS.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Neurônios Motores/patologia , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/patologia , Animais , Humanos , Chaperonas Moleculares/metabolismo , Neurônios Motores/metabolismo , Músculo Esquelético/inervação , Agregados Proteicos , Dobramento de Proteína , Proteoma/fisiologia
11.
Sci Rep ; 7(1): 14266, 2017 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-29079747

RESUMO

Tar DNA binding protein 43 (TDP-43) is the principal component of ubiquitinated protein inclusions present in nervous tissue of most cases of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies described a TDP-43A315T transgenic mouse model that develops progressive motor dysfunction in the absence of protein aggregation or significant motoneuron loss, questioning its validity to study ALS. Here we have further characterized the course of the disease in TDP-43A315T mice using a battery of tests and biochemical approaches. We confirmed that TDP-43 mutant mice develop impaired motor performance, accompanied by progressive body weight loss. Significant differences were observed in life span between genders, where females survived longer than males. Histopathological analysis of the spinal cord demonstrated a significant motoneurons loss, accompanied by axonal degeneration, astrogliosis and microglial activation. Importantly, histopathological alterations observed in TDP-43 mutant mice were similar to some characteristic changes observed in mutant SOD1 mice. Unexpectedly, we identified the presence of different species of disulfide-dependent TDP-43 aggregates in cortex and spinal cord tissue. Overall, this study indicates that TDP-43A315T transgenic mice develop key features resembling key aspects of ALS, highlighting its relevance to study disease pathogenesis.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Proteínas de Ligação a DNA/química , Dissulfetos/química , Demência Frontotemporal/patologia , Neurônios Motores/patologia , Multimerização Proteica , Medula Espinal/patologia , Esclerose Lateral Amiotrófica/metabolismo , Animais , Contagem de Células , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Demência Frontotemporal/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Córtex Pré-Frontal/metabolismo , Agregados Proteicos , Estrutura Quaternária de Proteína , Medula Espinal/metabolismo
12.
Prion ; 10(1): 50-6, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26864548

RESUMO

Disturbance of endoplasmic reticulum (ER) proteostasis is observed in Prion-related disorders (PrDs). The protein disulfide isomerase ERp57 is a stress-responsive ER chaperone up-regulated in the brain of Creutzfeldt-Jakob disease patients. However, the actual role of ERp57 in prion protein (PrP) biogenesis and the ER stress response remained poorly defined. We have recently addressed this question using gain- and loss-of-function approaches in vitro and animal models, observing that ERp57 regulates steady-state levels of PrP. Our results revealed that ERp57 modulates the biosynthesis and maturation of PrP but, surprisingly, does not contribute to the global cellular reaction against ER stress in neurons. Here we discuss the relevance of ERp57 as a possible therapeutic target in PrDs and other protein misfolding disorders.


Assuntos
Doenças Priônicas/metabolismo , Proteínas Priônicas/biossíntese , Proteínas Priônicas/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Estresse do Retículo Endoplasmático , Humanos , Modelos Biológicos , Proteínas Priônicas/análise , Proteínas Priônicas/química , Isomerases de Dissulfetos de Proteínas/química , Dobramento de Proteína
13.
Pain ; 157(6): 1346-1362, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26894912

RESUMO

We reported earlier that TNF-α, a proinflammatory cytokine implicated in many inflammatory disorders causing orofacial pain, increases the activity of Cdk5, a key kinase involved in brain development and function and recently found to be involved in pain signaling. To investigate a potential mechanism underlying inflammatory pain in trigeminal ganglia (TGs), we engineered a transgenic mouse model (TNF) that can conditionally overexpresses TNF-α upon genomic recombination by Cre recombinase. TNF mice were bred with Nav1.8-Cre mouse line that expresses the Cre recombinase in sensory neurons to obtain TNF-α:Nav1.8-Cre (TNF-α cTg) mice. Although TNF-α cTg mice appeared normal without any gross phenotype, they displayed a significant increase in TNF-α levels after activation of NFκB signaling in the TG. IL-6 and MCP-1 levels were also increased along with intense immunostaining for Iba1 and GFAP in TG, indicating the presence of infiltrating macrophages and the activation of satellite glial cells. TNF-α cTg mice displayed increased trigeminal Cdk5 activity, and this increase was associated with elevated levels of phospho-T407-TRPV1 and capsaicin-evocated Ca influx in cultured trigeminal neurons. Remarkably, this effect was prevented by roscovitine, an inhibitor of Cdk5, which suggests that TNF-α overexpression induced sensitization of the TRPV1 channel. Furthermore, TNF-α cTg mice displayed more aversive behavior to noxious thermal stimulation (45°C) of the face in an operant pain assessment device as compared with control mice. In summary, TNF-α overexpression in the sensory neurons of TNF-α cTg mice results in inflammatory sensitization and increased Cdk5 activity; therefore, this mouse model would be valuable for investigating the mechanism of TNF-α involved in orofacial pain.


Assuntos
Cálcio/metabolismo , Quinase 5 Dependente de Ciclina/metabolismo , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPV/metabolismo , Gânglio Trigeminal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Quimiocina CCL2/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Fator de Necrose Tumoral alfa/genética
14.
PLoS One ; 10(9): e0136620, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26361352

RESUMO

ERp57 (also known as grp58 and PDIA3) is a protein disulfide isomerase that catalyzes disulfide bonds formation of glycoproteins as part of the calnexin and calreticulin cycle. ERp57 is markedly upregulated in most common neurodegenerative diseases downstream of the endoplasmic reticulum (ER) stress response. Despite accumulating correlative evidence supporting a neuroprotective role of ERp57, the contribution of this foldase to the physiology of the nervous system remains unknown. Here we developed a transgenic mouse model that overexpresses ERp57 in the nervous system under the control of the prion promoter. We analyzed the susceptibility of ERp57 transgenic mice to undergo neurodegeneration. Unexpectedly, ERp57 overexpression did not affect dopaminergic neuron loss and striatal denervation after injection of a Parkinson's disease-inducing neurotoxin. In sharp contrast, ERp57 transgenic animals presented enhanced locomotor recovery after mechanical injury to the sciatic nerve. These protective effects were associated with enhanced myelin removal, macrophage infiltration and axonal regeneration. Our results suggest that ERp57 specifically contributes to peripheral nerve regeneration, whereas its activity is dispensable for the survival of a specific neuronal population of the central nervous system. These results demonstrate for the first time a functional role of a component of the ER proteostasis network in peripheral nerve regeneration.


Assuntos
Axônios/fisiologia , Isomerases de Dissulfetos de Proteínas/genética , Isomerases de Dissulfetos de Proteínas/metabolismo , Regeneração , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Corpo Estriado/metabolismo , Denervação , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Atividade Motora/genética , Degeneração Neural/genética , Degeneração Neural/patologia , Fenômenos Fisiológicos do Sistema Nervoso , Oxidopamina/farmacologia , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/fisiopatologia , Traumatismos dos Nervos Periféricos/reabilitação
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