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1.
Zhonghua Er Ke Za Zhi ; 57(11): 830-836, 2019 Nov 02.
Artigo em Chinês | MEDLINE | ID: mdl-31665836

RESUMO

Objective: To summarize the clinical and genetic features of ß-propeller protein-associated neurodegeneration (BPAN). Methods: The clinical data of 17 patients with BPAN with WDR45 gene variants were retrospectively collected at Children's Hospital of Fudan University, Peking University First Hospital, Capital Institute of Pediatrics, Shengjing Hospital of China Medical University and Shanghai Children's Hospital from June 2016 to December 2018, and their clinical manifestations, electroencephalogram, neuroimaging and genetics were analyzed. Results: Seventeen cases (13 females, 4 males), aged 1.1-8.8 years, were included. The median age of seizure onset was 14.5 months, from 3 months to 24 months of age, manifested with epileptic spasm in 6 cases and focal seizures in 5 cases. Eight patients had only one seizure type and 8 patients had two or more seizure types. Nine patients had complete remission of seizures. All 16 patients with seizures had developmental delay before the seizure onset, of whom 13 patients had moderate to severe seizures. The brain magnetic resonance imaging (MRI) was abnormal in 13 patients, including cerebral atrophy (10 cases) and thinning of the corpus callosum (9 cases). The brain magnetic susceptibility weighted imaging (SWI) in preschool stage showed prominent T2 hypointense signals in bilateral globus pallidus and brainstem ventral in two cases. Five seizure types (spasm, focal, absence, myodonic and generalized tonic clonic seizures)were found on ictal electroencephalogram(EEG) recordings. Compared to female patients(17(6-24) months of ege), male cases had earlier seizure onset (3, 4, 5, 18 months of age) . All patients had de novo variations in WDR45(6 nonsense, 4 frameshift, 3 missense and 4 splicing variations), with hemizygous variants in 3 males, mosaic variants in a male and heterozygous variants in 13 females, within which 5 variations had not been reported (c.977-1C>T,c.976+1G>C,c.10C>T,c.806del and c.110T>C). Conclusions: The patients with BPAN have profound developmental delay and are vulnerable to seizures. The male patients with BPAN tend to have more severer clinical phenotype than females. Early brain SWI could facilitate the timely diagnosis of this disease.


Assuntos
Proteínas de Transporte/genética , Epilepsia/genética , Doenças Neurodegenerativas/genética , China , Eletroencefalografia , Epilepsia/diagnóstico , Feminino , Humanos , Lactente , Masculino , Doenças Neurodegenerativas/diagnóstico por imagem , Estudos Retrospectivos , Convulsões
2.
Exp Suppl ; 111: 299-315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588537

RESUMO

Neurohypophyseal diabetes insipidus (DI) is most often caused by trauma, including operations, and infiltrating processes in the hypothalamic-pituitary region. Irradiation, ischemia, infections, or autoimmunity can also underlie the disease. Since the middle of the nineteenth century, familial forms of neurohypophyseal DI have been described. Most commonly, the disease is transmitted in an autosomal dominant fashion; very rarely, autosomal recessive inheritance has been observed. Hereditary neurohypophyseal DI is caused by mutations in the gene encoding the antidiuretic hormone vasopressin (AVP) and its carrier protein neurophysin II (NPII). Symptoms result from the lack of hormone, or from the inability of mutant AVP to activate its renal receptor, and respond to treatment with desmopressin (DDAVP). Dominant mutations cause retention of the hormone precursor in the endoplasmic reticulum (ER) of vasopressinergic neurons in the hypothalamus, resulting in cellular dysfunction and eventually neuronal death. This so-called neurotoxicity hypothesis was initially established on the basis of autopsy studies in affected humans and has been supported by heterologous cell culture expression experiments and murine knock-in models. Current data show that retained mutants fail to be eliminated by the cell's quality control system and accumulate in fibrillar aggregations within the ER. Autosomal dominant neurohypophyseal DI may thus be viewed as a neurodegenerative disease confined to vasopressinergic neurons.


Assuntos
Diabetes Insípido Neurogênico/genética , Doenças Neurodegenerativas/genética , Animais , Retículo Endoplasmático/patologia , Humanos , Camundongos , Mutação
3.
Mol Biol (Mosk) ; 53(5): 755-773, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31661476

RESUMO

Dysregulated proinflammatory cytokine expression may result in the development of severe pathologies, such as rheumatoid arthritis, psoriasis, and neurodegenerative diseases. Transgenic mice and, in particular, those with controllable systemic overexpression of proinflammatory cytokines have recently become an essential instrument to study the molecular mechanisms underlying disease development. Importantly, many of the models are humanized by introducing a human cytokine gene, while leaving or removing the respective endogenous mouse gene. Humanized mice are especially valuable for biomedical research as they provide a relevant model to develop therapies based on blocking the pathogenic activity of a cytokine or to establish the functional significance of genome polymorphisms. The review discusses the available humanized mouse models with overexpression of key proinflammatory cytokines (TNF, IL-ip, and IL-6) and inflammatory cytokines with more specific functions (IL-8, IL-17, and IL-32) and their significance for basic and clinical research.


Assuntos
Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Regulação para Cima , Animais , Artrite Reumatoide/genética , Citocinas/biossíntese , Humanos , Camundongos , Camundongos Transgênicos , Doenças Neurodegenerativas/genética , Psoríase/genética
4.
Postepy Biochem ; 65(3): 217-223, 2019 10 01.
Artigo em Polonês | MEDLINE | ID: mdl-31643169

RESUMO

Transposable elements (TEs) are the sequences that are able to "jump" across the genome. They are found in virtually all organisms including human. Although in human, the majority of TEs lost their ability to autonomous transposition, they make up almost half of our genome, and played important roles in genome evolution. Fast progress in deep sequencing and functional analysis has revealed the importance of domes­ticated copies of transposable elements, including their regulatory sequences, transcripts and proteins in normal cells functioning. However, a growing numer of evidence suggest the involvment of TEs in development and progression of autoimmune and neurodegenerative disaeses as well as in many types of cancer. In this review we summarize the current state of knowledge about the LTR retroelements: endogenous retroviruses (ERVs) and Ty3/Gypsy retrotransposons, and their role in human organism.


Assuntos
Genoma Humano/genética , Retroelementos/genética , Doenças Autoimunes/genética , Retrovirus Endógenos/genética , Evolução Molecular , Humanos , Neoplasias/genética , Doenças Neurodegenerativas/genética , Sequências Repetidas Terminais/genética
5.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(9): 851-855, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31506141

RESUMO

Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disease. Two boys aged 3 years and 4 years and 2 months respectively, were admitted to the hospital due to delayed mental and motor development. There were no abnormalities at birth, and both children had low muscle strength and tension on admission. One child was not able to stand alone and had impaired vision. Electromyography showed neurogenic damage, and head MRI revealed cerebellar atrophy. High-throughput sequencing revealed compound heterozygous mutations in the PLA2G6 gene in the two children. The mutations (IVS11-1G>T and c.1984C>G) in one child were new mutations, and immunohistochemistry showed a reduction in the protein expression of PLAG6 in the muscular tissue of this child. INAD has the main clinical manifestations of psychomotor developmental regression and cerebellar atrophy. High-throughput sequencing can help with clinical diagnosis.


Assuntos
Fosfolipases A2 do Grupo VI/genética , Distrofias Neuroaxonais , Doenças Neurodegenerativas , Pré-Escolar , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação , Distrofias Neuroaxonais/genética , Doenças Neurodegenerativas/genética
7.
Nat Neurosci ; 22(9): 1383-1388, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358992

RESUMO

Nucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. Unconventional translation (RAN translation) of C9orf72 repeats generates dipeptide repeat proteins that can cause neurodegeneration. We performed a genetic screen for regulators of RAN translation and identified small ribosomal protein subunit 25 (RPS25), presenting a potential therapeutic target for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia and other neurodegenerative diseases caused by nucleotide repeat expansions.


Assuntos
Proteína C9orf72/genética , Doenças Neurodegenerativas/genética , Proteínas Ribossômicas/genética , Animais , Expansão das Repetições de DNA/genética , Humanos , Biossíntese de Proteínas
8.
BMC Neurol ; 19(1): 153, 2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31279336

RESUMO

BACKGROUND: Multiple Mitochondrial Dysfunctions Syndrome 4 (MMDS4) is manifested as a result of ISCA2 mutations. ISCA2 is a vital component of 4Fe-4S clusters assembly machine. Therefore, in MMDS4 patients, deficient mitochondrial respiratory chain complexes I and II, Aconitase and Succinate dehydrogenase of Kerbs cycle and Lipoic Acid Synthetase in the biosynthesis of lipoic acid are expected. CASE PRESENTATIONS: A 7 months boy in an Iranian consanguineous family with progressive neurodegenerative problems was referred to us. Primarily, general laboratory tests, Abdomen ultrasonography and brain magnetic resonance imaging were performed. In order to find out the genetic problem in this case Whole Exome Sequencing (WES) following by Sanger sequencing was carried out. A novel variant (c.355G > A, p.Ala119Thr) in ISCA2 gene was identified by WES in the proband. Confirmation and segregation in the family for this variant was performed by Sanger sequencing. In-Silico prediction of the ISCA2 secondary structure showed that a helix motif in the Fe-S biosynthesis domain of ISCA2 protein will be eliminated as a result of this variant. CONCLUSIONS: We reported the first patient with ISCA2 variant in Iranian population and the third one in the world reported for ISCA2 gene, so far associated with early-onset mitochondrial neurodegeneration. However further functional studies on this variant or finding it in other patients with similar clinical problems are needed to confirm the pathogenicity of this variant.


Assuntos
Proteínas com Ferro-Enxofre/genética , Doenças Mitocondriais/genética , Complexo I de Transporte de Elétrons/genética , Humanos , Lactente , Irã (Geográfico) , Imagem por Ressonância Magnética , Masculino , Mitocôndrias , Doenças Mitocondriais/diagnóstico por imagem , Mutação , Doenças Neurodegenerativas/genética
9.
Intern Med ; 58(13): 1851-1858, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257275

RESUMO

Objective Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the progressive loss of the upper and lower motor neurons that progresses to paralysis of almost all skeletal muscles of the extremities, bulbar, and respiratory system. Although most ALS cases are sporadic, about 10% are dominantly inherited. We herein report an atypical phenotype of familial ALS (fALS). To elucidate the phenotype-genotype correlation of this atypical phenotype of fALS, clinical and genetic investigations were performed. Methods and Patients Five sibling patients (three men, two women) from a Japanese family and one healthy sibling (a woman) were clinically interviewed and examined. Genetic analyses, including genome-wide linkage analyses and whole-exome sequencing, were performed using genomic DNA extracted from the peripheral blood samples of these siblings. Results The clinical features of fALS are characterized by slow progression (mean duration of the disease±standard deviation [SD]: 19.6±3.9 years) and lower extremities-predominant late-onset muscular weakness (mean onset of muscular weakness±SD: 52.8±2.6 years). Genetic analyses revealed novel heterozygous missense mutations of c.2668C>T, p.R890C in the PLEC gene and c.421G>C, p.V141L in the ST3GAL6 gene in all affected siblings. Conclusion A new atypical fALS family with a benign clinical course is herein reported. We identified two candidate gene mutations of PLEC and ST3GAL6 linked to this phenotype.


Assuntos
Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/mortalidade , Predisposição Genética para Doença , Neurônios Motores/fisiologia , Debilidade Muscular/fisiopatologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/fisiopatologia , Grupo com Ancestrais do Continente Asiático , Evolução Fatal , Feminino , Genótipo , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Mutação , Doenças Neurodegenerativas/mortalidade , Fenótipo
10.
Yakugaku Zasshi ; 139(6): 853-859, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31155525

RESUMO

In most mammalian species, adult neurogenesis appears to occur only in the olfactory bulb and hippocampal dentate gyrus, where neural stem/progenitor cells exist to create new neurons. The discovery of multi-potential neural stem/progenitor cells (NPCs) in the adult brain has precipitated a novel therapeutic strategy for harnessing these endogenous cells to aid in recovery from neurodegenerative disorders. During neurodegeneration, a plethora of endogenous factors, including cytokines, chemokines, neurotransmitters, blood-derived factors, and reactive oxygen species, are released by the activation of resident microglia, astrocytes, and infiltrating peripheral macrophages. It is interesting that these endogenous factors affect the proliferation, migration, differentiation, and survival of newly generated cells involved in the incorporation of newly generated neurons into the brain's circuitry. The unique profile of these endogenous factors can vary the degree of neuroregeneration after neurodegeneration. We show that adult neurogenesis-activating signals are regulated by endogenous factors produced during neurodegeneration.


Assuntos
Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Terapia de Alvo Molecular , Células-Tronco Multipotentes/fisiologia , Células-Tronco Neurais/fisiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/terapia , Neurogênese/genética , Neurogênese/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Animais , Encéfalo/citologia , Quimiocinas/fisiologia , Citocinas/fisiologia , Humanos , Camundongos , Regeneração Nervosa/genética , Regeneração Nervosa/fisiologia , Neurotransmissores/fisiologia , Espécies Reativas de Oxigênio
11.
BMC Vet Res ; 15(1): 192, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182094

RESUMO

BACKGROUND: Degenerative myelopathy (DM) is a progressive neurodegenerative disease frequently found in Pembroke Welsh Corgis (PWCs). Most DM-affected PWCs are homozygous for the mutant superoxide dismutase 1 (SOD1) allele; however, the genetic examination for the SOD1 mutation does not exclusively detect symptomatic dogs. In order to identify novel biomarkers, the plasma microRNA (miRNA) profiles of PWCs with DM were investigated. RESULTS: Quantification of the plasma levels of 277 miRNAs by an RT-qPCR array identified 11 up-regulated miRNAs and 7 down-regulated miRNAs in DM-affected PWCs from those in wild-type SOD1 PWCs. A pathway analysis identified 3 miRNAs: miR-26b, miR-181a, and miR-196a, which potentially regulate several genes associated with SOD1. In order to validate the diagnostic accuracy of the candidate miRNAs in the aged PWC population, candidate miRNAs in plasma were measured by RT-qPCR and a receiver operating characteristic (ROC) curve analysis was performed. miR-26b had the largest area under the ROC curve for distinguishing DM PWCs from healthy PWCs (sensitivity, 66.7%; specificity, 87.0%). The plasma level of miR-26b was significantly higher in the DM group than in the healthy control group. A positive correlation was observed between increases in the plasma level of miR-26b and disease progression. CONCLUSIONS: These results suggest that plasma miR-26b is a potential novel diagnostic biomarker of DM.


Assuntos
Doenças do Cão/genética , MicroRNAs/sangue , Doenças Neurodegenerativas/veterinária , Animais , Biomarcadores/sangue , Progressão da Doença , Doenças do Cão/diagnóstico , Cães , Feminino , Masculino , Mutação , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Superóxido Dismutase-1/genética
12.
Cell Mol Life Sci ; 76(20): 3987-4008, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31227845

RESUMO

Polyamines (PAs) are essential organic polycations for cell viability along the whole phylogenetic scale. In mammals, they are involved in the most important physiological processes: cell proliferation and viability, nutrition, fertility, as well as nervous and immune systems. Consequently, altered polyamine metabolism is involved in a series of pathologies. Due to their pathophysiological importance, PA metabolism has evolved to be a very robust metabolic module, interconnected with the other essential metabolic modules for gene expression and cell proliferation/differentiation. Two different PA sources exist for animals: PA coming from diet and endogenous synthesis. In the first section of this work, the molecular characteristics of PAs are presented as determinant of their roles in living organisms. In a second section, the metabolic specificities of mammalian PA metabolism are reviewed, as well as some obscure aspects on it. This second section includes information on mammalian cell/tissue-dependent PA-related gene expression and information on crosstalk with the other mammalian metabolic modules. The third section presents a synthesis of the physiological processes described as modulated by PAs in humans and/or experimental animal models, the molecular bases of these regulatory mechanisms known so far, as well as the most important gaps of information, which explain why knowledge around the specific roles of PAs in human physiology is still considered a "mysterious" subject. In spite of its robustness, PA metabolism can be altered under different exogenous and/or endogenous circumstances so leading to the loss of homeostasis and, therefore, to the promotion of a pathology. The available information will be summarized in the fourth section of this review. The different sections of this review also point out the lesser-known aspects of the topic. Finally, future prospects to advance on these still obscure gaps of knowledge on the roles on PAs on human physiopathology are discussed.


Assuntos
Fertilidade/fisiologia , Gastroenteropatias/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Poliaminas/metabolismo , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/metabolismo , Animais , Carboxiliases/genética , Carboxiliases/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Gastroenteropatias/genética , Gastroenteropatias/fisiopatologia , Regulação da Expressão Gênica , Humanos , Hidrolases/genética , Hidrolases/metabolismo , Mamíferos , Neoplasias/genética , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Poliaminas/administração & dosagem , Poliaminas/farmacologia
13.
Cell Mol Life Sci ; 76(20): 4023-4042, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31236625

RESUMO

Succinate dehydrogenase (SDH) also known as complex II or succinate:quinone oxidoreductase is an enzyme involved in both oxidative phosphorylation and tricarboxylic acid cycle; the processes that generate energy. SDH is a multi-subunit enzyme which requires a series of proteins for its proper assembly at several steps. This enzyme has medical significance as there is a broad range of human diseases from cancers to neurodegeneration related to SDH malfunction. Some of these disorders have recently been linked to defective assembly factors, reinvigorating further research in this area. Apart from that this enzyme has agricultural importance as many fungicides have been/will be designed targeting specifically this enzyme in plant fungal pathogens. In addition, we speculate it might be possible to design novel fungicides specifically targeting fungal assembly factors. Considering the medical and agricultural implications of SDH, the aim of this review is an overview of the SDH assembly factors and critical analysis of controversial issues around them.


Assuntos
Mitocôndrias/enzimologia , Neoplasias/enzimologia , Doenças Neurodegenerativas/enzimologia , Subunidades Proteicas/química , Proteínas/genética , Succinato Desidrogenase/química , Animais , Ciclo do Ácido Cítrico/genética , Coenzimas/química , Coenzimas/metabolismo , Flavina-Adenina Dinucleotídeo/química , Flavina-Adenina Dinucleotídeo/metabolismo , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Fungos , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Expressão Gênica , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Mitocôndrias/genética , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Fosforilação Oxidativa , Plantas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Proteínas/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo
14.
J Clin Neurosci ; 68: 266-267, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31221578

RESUMO

Niemann Pick type C (NP-C) is an autosomal recessive neurovisceral lysosomal storage disorder caused by NPC1 and NPC2 gene mutations. We screened for NP-C 24 patients with Progressive Supranuclear Palsy and 10 with Multiple System Atrophy cerebellar type (MSA-C). Among PSP patients, no NPC1 or NPC2 gene variants were detected. One patient with MSA-C (10%) resulted to carry a pathogenic missense NPC1 gene mutation (p.C184Y) in heterozygous state. NPC1 genes variants might represent a risk or susceptibility factor in the development of α-synucleinopathies such as MSA. The common pattern of lysosomal dysfunction might explain the pathophysiological link between these disorders.


Assuntos
Atrofia de Múltiplos Sistemas/genética , Doença de Niemann-Pick Tipo C/complicações , Paralisia Supranuclear Progressiva/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Mutação de Sentido Incorreto , Doenças Neurodegenerativas/genética , Doença de Niemann-Pick Tipo C/genética
15.
Cell Mol Life Sci ; 76(20): 3953-3967, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31250034

RESUMO

The brain tissue has only a limited capacity for generating new neurons. Therefore, to treat neurological diseases, there is a need of other cell sources for brain repair. Different sources of cells have been subject of intense research over the years, including cells from primary tissue, stem cell-derived cells and reprogrammed cells. As an alternative, direct reprogramming of resident brain cells into neurons is a recent approach that could provide an attractive method for treating brain injuries or diseases as it uses the patient's own cells for generating novel neurons inside the brain. In vivo reprogramming is still in its early stages but holds great promise as an option for cell therapy. To date, both inhibitory and excitatory neurons have been obtained via in vivo reprogramming, but the precise phenotype or functionality of these cells has not been analysed in detail in most of the studies. Recent data shows that in vivo reprogrammed neurons are able to functionally mature and integrate into the existing brain circuitry, and compose interneuron phenotypes that seem to correlate to their endogenous counterparts. Interneurons are of particular importance as they are essential in physiological brain function and when disturbed lead to several neurological disorders. In this review, we describe a comprehensive overview of the existing studies involving brain repair, including in vivo reprogramming, with a focus on interneurons, along with an overview on current efforts to generate interneurons for cell therapy for a number of neurological diseases.


Assuntos
Lesões Encefálicas/terapia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Interneurônios/citologia , Doenças Neurodegenerativas/terapia , Regeneração/fisiologia , Animais , Biomarcadores/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Transdiferenciação Celular , Reprogramação Celular , Fibroblastos/citologia , Fibroblastos/metabolismo , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Injeções Intraventriculares , Interneurônios/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurogênese/genética , Transplante de Células-Tronco/métodos
16.
J Am Assoc Nurse Pract ; 31(5): 282-284, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083007

RESUMO

Neurodegenerative diseases are more common in older individuals and are progressively debilitating. Due to the aging of the American population, the burden of neurodegenerative diseases on the health care infrastructure will likely significantly increase in the near future. Genetic science has advanced our understanding of the pathology driving these diseases thereby informing new, individualized care paradigms. Although translation into clinical practice is slow, there are a few examples of instances where precision medicine is making a difference in the care of patients with neurodegenerative diseases that may be driven by genetic background. This article provides a brief overview of the current knowledge of genetic influences on two common neurodegenerative diseases, Alzheimer Disease and Parkinson Disease, as well as ways this knowledge is being tested for a precision medicine approach to care.


Assuntos
Doenças Neurodegenerativas/genética , Doença de Alzheimer/genética , Doença de Alzheimer/enfermagem , Humanos , Programas de Rastreamento/métodos , Doenças Neurodegenerativas/enfermagem , Doença de Parkinson/genética , Doença de Parkinson/enfermagem , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Fatores de Risco
17.
Mol Med Rep ; 20(1): 813-829, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115526

RESUMO

Infrapatellar fat pad­derived stem cells (IFPSCs) are emerging as an alternative to adipose tissue­derived stem cells (ADSCs) from other sources. They are a reliable source of autologous stem cells obtained from medical waste that are suitable for use in cell­based therapy, tissue engineering and regenerative medicine. Such clinical applications require a vast number of high­quality IFPSCs. Unlike embryonic stem cells (ESCs), ADSCs and IFPSCs have limited population doubling capacity; however, in vitro expansion of primary IFPSCs through multiple passages (referred to as P) is a crucial step to acquire the desired population of cells. The present study investigated the effect of multiple passages on the stemness of IFPSCs during expansion and the possibility of predicting the loss of stemness using certain markers. IFPSCs were isolated from infrapatellar fat pad tissue resected during knee arthroplasty performed on aged patients (>65 years old). These cells from the stromal vascular fraction were serially passaged to at least to P7, and their stemness characteristics were examined at each passage. It was observed that IFPSCs maintained their spindle­shaped morphology, self­renewability and homogeneity at P2­4. Furthermore, immunostaining revealed that these cells expressed mesenchymal stem cell (CD166, CD90 and CD105) and ESC markers [Sox2, Nanog, Oct4 and nucleostemin (NS)], whereas the hematopoietic stem cell marker CD45 was absent. These cells were also able to differentiate into the three germ layer cell types, thus confirming their ability to generate clinical grade cells. The findings indicated that prolonged culture of IFPSCs (P>6) led to the loss of the stem cell proliferative marker NS, with an increased population doubling time and progression toward neuronal differentiation, acquiring a neurogenic phenotype. Additionally, IFPSCs demonstrated an inherent ability to secrete neurotrophic factors and express receptors for these factors, which is the cause of neuronal differentiation at later passages. Therefore, these findings validated NS as a prognostic indicator for impaired stemness and identified IFPSCs as a promising source for cell­based therapy, particularly for neurodegenerative diseases.


Assuntos
Biomarcadores , Autorrenovação Celular/genética , Proteínas de Ligação ao GTP/genética , Células-Tronco Mesenquimais/citologia , Proteínas Nucleares/genética , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Idoso , Diferenciação Celular/genética , Proliferação de Células/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Células-Tronco Mesenquimais/metabolismo , Fatores de Crescimento Neural/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Patela/citologia , Patela/metabolismo , Prognóstico
18.
Nat Commun ; 10(1): 1817, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31000720

RESUMO

Neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Huntington's disease manifest with the neuronal accumulation of toxic proteins. Since autophagy upregulation enhances the clearance of such proteins and ameliorates their toxicities in animal models, we and others have sought to re-position/re-profile existing compounds used in humans to identify those that may induce autophagy in the brain. A key challenge with this approach is to assess if any hits identified can induce neuronal autophagy at concentrations that would be seen in humans taking the drug for its conventional indication. Here we report that felodipine, an L-type calcium channel blocker and anti-hypertensive drug, induces autophagy and clears diverse aggregate-prone, neurodegenerative disease-associated proteins. Felodipine can clear mutant α-synuclein in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug. This is associated with neuroprotection in mice, suggesting the promise of this compound for use in neurodegeneration.


Assuntos
Autofagia/efeitos dos fármacos , Reposicionamento de Medicamentos , Felodipino/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Animais , Animais Geneticamente Modificados , Linhagem Celular , Córtex Cerebral/citologia , Córtex Cerebral/patologia , Modelos Animais de Doenças , Embrião de Mamíferos , Embrião não Mamífero , Felodipino/uso terapêutico , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Cultura Primária de Células , Suínos , Porco Miniatura , Resultado do Tratamento , Peixe-Zebra , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
19.
Magn Reson Imaging ; 60: 52-67, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30940494

RESUMO

To understand multifactorial conditions such as Alzheimer's disease (AD) we need brain signatures that predict the impact of multiple pathologies and their interactions. To help uncover the relationships between pathology affected brain circuits and cognitive markers we have used mouse models that represent, at least in part, the complex interactions altered in AD, while being raised in uniform environments and with known genotype alterations. In particular, we aimed to understand the relationship between vulnerable brain circuits and memory deficits measured in the Morris water maze, and we tested several predictive modeling approaches. We used in vivo manganese enhanced MRI traditional voxel based analyses to reveal regional differences in volume (morphometry), signal intensity (activity), and magnetic susceptibility (iron deposition, demyelination). These regions included hippocampus, olfactory areas, entorhinal cortex and cerebellum, as well as the frontal association area. The properties of these regions, extracted from each of the imaging markers, were used to predict spatial memory. We next used eigenanatomy, which reduces dimensionality to produce sets of regions that explain the variance in the data. For each imaging marker, eigenanatomy revealed networks underpinning a range of cognitive functions including memory, motor function, and associative learning, allowing the detection of associations between context, location, and responses. Finally, the integration of multivariate markers in a supervised sparse canonical correlation approach outperformed single predictor models and had significant correlates to spatial memory. Among a priori selected regions, expected to play a role in memory dysfunction, the fornix also provided good predictors, raising the possibility of investigating how disease propagation within brain networks leads to cognitive deterioration. Our cross-sectional results support that modeling approaches integrating multivariate imaging markers provide sensitive predictors of AD-like behaviors. Such strategies for mapping brain circuits responsible for behaviors may help in the future predict disease progression, or response to interventions.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Modelos Animais de Doenças , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética , Doença de Alzheimer/patologia , Animais , Comportamento Animal , Biomarcadores , Encéfalo/patologia , Mapeamento Encefálico/métodos , Cognição , Disfunção Cognitiva/patologia , Meios de Contraste , Estudos Transversais , Progressão da Doença , Fórnice/patologia , Genótipo , Hipocampo/patologia , Magnetismo , Aprendizagem em Labirinto , Memória , Transtornos da Memória/patologia , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/genética , Neuroimagem , Memória Espacial
20.
Immunity ; 50(4): 955-974, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995509

RESUMO

Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and emerging mechanisms for three key immune pathways implicated in disease, the growth factor TGF-ß, the complement cascade, and the extracellular receptor TREM2. These immune signaling pathways are important under both healthy and neurodegenerative conditions, and recent work has highlighted new functional aspects of their signaling. Finally, we assess future directions for immune-related research in neurodegeneration and potential avenues for immune-related therapies.


Assuntos
Doenças Neurodegenerativas/imunologia , Transdução de Sinais/imunologia , Envelhecimento/imunologia , Animais , Ativação do Complemento , Progressão da Doença , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Gliose/imunologia , Gliose/patologia , Humanos , Imunidade Inata , Inflamação/imunologia , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/imunologia , Modelos Imunológicos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/terapia , Agregação Patológica de Proteínas/imunologia , Receptores Imunológicos/imunologia , Fator de Crescimento Transformador beta/imunologia
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