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1.
Brain Nerve ; 71(10): 1071-1079, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31588051

RESUMO

Next generation sequencing (NGS) technology has dramatically influenced the field of omics studies, such as genomics and transcriptomics. It is now possible to access a significant number of previously known and novel genomic variants through NGS. Although the effective manipulation and accurate interpretation of the inordinate amount of data may pose a considerable challenge, it enables us to identify specific genes responsible for causing or influencing the susceptibility to a plethora of diseases. Alzheimer's disease (AD) is the most common etiology of dementia in the elderly (approximately 60-70%). The current research trend of AD genetics focuses on the analysis of rare variants (allelic frequency <1%) instead of common variants (allelic frequency >1%) to identify AD-associated genes/variants. A number of genes (such as TREM2, ABCA7, SORL1) that carry rare pathogenic variants have reportedly conferred susceptibility to AD with stronger genetic risk effects (odds ratio >2.0). Here, we are going to introduce a small part of the latest many attractive findings about AD genetic researches.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Frequência do Gene , Testes Genéticos , Genômica , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Receptores Imunológicos/genética
2.
Nat Rev Dis Primers ; 5(1): 30, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048702

RESUMO

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or other AChR-related proteins in the postsynaptic muscle membrane. Localized or general muscle weakness is the predominant symptom and is induced by the antibodies. Patients are grouped according to the presence of antibodies, symptoms, age at onset and thymus pathology. Diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, although a detailed clinical and neurophysiological examination is important in antibody-negative patients. MG therapy should be ambitious and aim for clinical remission or only mild symptoms with near-normal function and quality of life. Treatment should be based on MG subgroup and includes symptomatic treatment using acetylcholinesterase inhibitors, thymectomy and immunotherapy. Intravenous immunoglobulin and plasma exchange are fast-acting treatments used for disease exacerbations, and intensive care is necessary during exacerbations with respiratory failure. Comorbidity is frequent, particularly in elderly patients. Active physical training should be encouraged.


Assuntos
Miastenia Gravis/diagnóstico , Miastenia Gravis/terapia , Acetilcolinesterase/genética , Acetilcolinesterase/fisiologia , Corticosteroides/uso terapêutico , Agrina/genética , Agrina/fisiologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Autoanticorpos/análise , Autoanticorpos/sangue , Biomarcadores/análise , Biomarcadores/sangue , Blefaroptose/etiologia , Colágeno/genética , Colágeno/fisiologia , Cortactina/genética , Cortactina/fisiologia , Eletromiografia/métodos , Humanos , Canal de Potássio Kv1.4/genética , Canal de Potássio Kv1.4/fisiologia , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/fisiologia , Proteínas Musculares/genética , Proteínas Musculares/fisiologia , Miastenia Gravis/fisiopatologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/fisiologia , Receptores Colinérgicos/genética , Receptores Colinérgicos/fisiologia , Receptores Nicotínicos/genética , Fatores de Risco , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia
3.
Nat Commun ; 10(1): 2340, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138794

RESUMO

The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.


Assuntos
Neoplasias da Mama/genética , Carcinoma Intraductal não Infiltrante/genética , Carcinoma de Células de Transição/genética , Membrana Celular/metabolismo , Endossomos/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Receptor ErbB-2/metabolismo , Neoplasias da Bexiga Urinária/genética , Animais , Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma de Células de Transição/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Proteínas Relacionadas a Receptor de LDL/metabolismo , Lisossomos/metabolismo , Células MCF-7 , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Nus , Transplante de Neoplasias , Transporte Proteico , Neoplasias da Bexiga Urinária/metabolismo
4.
BMC Neurol ; 19(1): 97, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092209

RESUMO

BACKGROUND: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare clinical entity, characterized by headaches, seizures, rapidly progressive cognitive decline, behavioral changes and magnetic resonance imaging (MRI) findings underlying the autoimmune and inflammatory reaction at the level of CAA-affected vessel. CAA-ri is likely responsive to corticosteroid. MRI shows asymmetric and multifocal white matter hyperintensity (WMH) lesions and multiple cerebral microbleeds. Apolipoprotein E (ApoE) ε4 homozygosity is associated with CAA-ri strongly [Neurology 68(17):1411-1416, 2007, Ann Neurol 73(4):449-458, 2013, J Alzheimers Dis 44(4):1069-1074, 2015]. SORL1 processes a causal involvement in Alzheimer's disease (AD) as a proposed modulator of the amyloid precursor protein (APP). It is unclear whether SORL1 is involved with CAA-ri or not. CASE PRESENTATION: A 48-year-old woman suffered from a one-day history of a headache, nausea, and vomiting. Neurological examination revealed normal. We diagnosed this case as probable CAA-ri according to the clinic manifestations and MRI. Gene detection indicated a rare variant in SORL1 and ApoE ε4 homozygosity. When treated with corticosteroid, the patient's clinical symptoms and MRI manifestations were almost relieved. However, when keeping the corticosteroid withdrawal for three months, the patient relapsed with a headache and typical images on MRI emerged. Corticosteroid therapy was effective again. Unfortunately, susceptibility weighted imaging (SWI) showed increased microbleeds. With tapering corticosteroid slowly, no recurrence was found on this patient with four-month follow-up. CONCLUSION: A variant of SORL1 may be associated with CAA-ri, recurrence of disease could be detected with MRI by an increased microbleeds. Our case report suggests that corticosteroid therapy might be effective for CAA-ri.


Assuntos
Angiopatia Amiloide Cerebral/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/patologia , Feminino , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade
5.
J Biol Chem ; 294(17): 6899-6911, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30842262

RESUMO

Sclerostin exerts profound local control over bone acquisition and also mediates endocrine communication between fat and bone. In bone, sclerostin's anti-osteoanabolic activity is enhanced by low-density lipoprotein receptor-related protein 4 (Lrp4), which facilitates its interaction with the Lrp5 and Lrp6 Wnt co-receptors. To determine whether Lrp4 similarly affects sclerostin's endocrine function, we examined body composition as well as glucose and fatty acid metabolism in mice rendered deficient of Lrp4 in the adipocyte (AdΔLrp4) or the osteoblast (ObΔLrp4). AdΔLrp4 mice exhibit a reduction in adipocyte hypertrophy and improved glucose and lipid homeostasis, marked by increased glucose and insulin tolerance and reduced serum fatty acids, and mirror the effect of sclerostin deficiency on whole-body metabolism. Indeed, epistasis studies place adipocyte-expressed Lrp4 and sclerostin in the same genetic cascade that regulates adipocyte function. Intriguingly, ObΔLrp4 mice, which exhibit dramatic increases in serum sclerostin, accumulate body fat and develop impairments in glucose tolerance and insulin sensitivity despite development of a high bone mass phenotype. These data indicate that expression of Lrp4 by both the adipocyte and osteoblast is required for normal sclerostin endocrine function and that the impact of sclerostin deficiency on adipocyte physiology is distinct from the effect on osteoblast function.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adipócitos/metabolismo , Composição Corporal , Proteínas Relacionadas a Receptor de LDL/metabolismo , Osteoblastos/metabolismo , Animais , Células Cultivadas , Epistasia Genética , Ácidos Graxos/metabolismo , Homeostase , Proteínas Relacionadas a Receptor de LDL/genética , Camundongos
6.
Int J Geriatr Psychiatry ; 34(5): 692-699, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30706571

RESUMO

OBJECTIVE: While a number of single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) or cognitive impairment have been identified, independent replications remain the only way to validate proposed signals. We investigated SNPs in candidate genes associated with either cognitive impairment or AD pathogenesis and their relationships with probable dementia (PD) in the Women's Health Initiative Memory Study (WHIMS). METHODS: We analyzed 96 SNPs across five genes (APOE/TOMM40, BDNF, COMT, SORL1, and KIBRA) in 2857 women (ages ≥65) from the WHIMS randomized trials of hormone therapy using a custom Illumina GoldenGate assay; 19% of the sample were MCI (N = 165) or PD (N = 387), and the remaining 81% were free of cognitive impairment. SNP associations were evaluated for PD in non-Hispanic whites adjusting for age and HT using logistic regression under an additive genetic model. RESULTS: One SNP (rs157582), located in the TOMM40 gene nearby APOE, was associated with the PD phenotype based on a P value accounting for multiple comparisons. An additional 12 SNPs were associated with the PD phenotype at P ≤ 0.05 (APOE: rs405509, rs439401; TOMM40: rs8106922, and KIBRA: rs4320284, rs11740112, rs10040267, rs13171394, rs6555802, rs2241368, rs244904, rs6555805, and rs10475878). Results of the sensitivity analyes excluding MCI were similar, with addition of COMT rs737865 and BDNF rs1491850 (P ≤ 0.05). CONCLUSIONS: Our results in older women provide supporting evidence that the APOE/TOMM40 genes confer dementia risk and extend these findings to COMT, BDNF, and KIBRA. Our findings may lead to a better understanding of the role these genes play in cognition and cognitive impairment.


Assuntos
Doença de Alzheimer/genética , Disfunção Cognitiva/genética , Demência/genética , Predisposição Genética para Doença , Idoso , Apolipoproteínas E/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Catecol O-Metiltransferase/genética , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Saúde da Mulher
7.
Mol Biol Rep ; 46(2): 1701-1707, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30684189

RESUMO

Numerous genetic evidence has pointed out that variations in cholesterol-related genes may be associated with an Alzheimer's disease (AD) risk. We aimed to investigate the association between polymorphisms in several cholesterol-related genes [APOA5 (rs662799), APOC1 (rs11568822), APOD (rs1568565), CH25H (rs13500), LDLR (rs5930), SORL1 (rs2282649)] and AD in a cohort of Turkish patients. The study group consisted of 257 AD patients (mean age: 75.9 years ± 10.4) and 414 controls (mean age: 62.2 years ± 13.1). Genotyping was performed by quantitative real-time polymerase chain reaction using hydrolysis probes. Our results showed that the 'TT' genotype of CH25H rs13500 polymorphism was significantly more frequent in the AD group (p < 0.001) and individuals carrying the CH25H 'T' allele had an increased risk for AD (OR 3.07, 95% CI 2.13-4.44, p = 2.20e-09) independently from age, gender and APOE ε4 allele. Moreover, this risk was excessively increased (OR 14.04, 95% CI 6.99-28.23, p = 9.78e-14) in the presence of APOE ε4 allele. The 'ins/ins' genotype of APOC1 rs11568822 was significantly more frequent in the AD group compared to controls (p = 1.95e-08). However, this increased AD risk in 'ins/ins' carriers was found to be dependent on their APOE ε4 carrier status. No significant associations were found in allele and genotype distributions of APOA5, APOD, LDLR and SORL1 gene polymorphisms. Our results suggest that the association between APOC1 'ins/ins' genotype and AD risk can be explained by linkage disequilibrium with the APOE locus. CH25H rs13500 polymorphism is associated with an AD risk in the Turkish population and CH25H might have a role in the pathogenesis of AD together with, and independently from APOE.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína C-I/genética , Esteroide Hidroxilases/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/metabolismo , Apolipoproteína A-V/genética , Apolipoproteína E4/genética , Apolipoproteínas D/genética , Apolipoproteínas E/genética , Estudos de Casos e Controles , Colesterol/genética , Colesterol/metabolismo , Estudos de Coortes , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Genótipo , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Desequilíbrio de Ligação , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Receptores de LDL/genética , Esteroide Hidroxilases/metabolismo , Turquia/epidemiologia
8.
G3 (Bethesda) ; 9(2): 463-471, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30622122

RESUMO

Post-traumatic stress disorder is a concerning psychobehavioral disorder thought to emerge from the complex interaction between genetic and environmental factors. For soldiers exposed to combat, the risk of developing this disorder is twofold and diagnosis is often late, when much sequela has set in. To be able to identify and diagnose in advance those at "risk" of developing post-traumatic stress disorder, would greatly taper the gap between late sequelae and treatment. Therefore, this study sought to determine whether the transcriptome can be used to track the development of post-traumatic stress disorder in this unique and susceptible cohort of individuals. Gene expression levels in peripheral blood samples from 85 Canadian infantry soldiers (n = 58 participants negative for symptoms of post-traumatic stress disorder and n = 27 participants with symptoms of post-traumatic stress disorder) following return from deployment to Afghanistan were determined using RNA sequencing technology. Count-based gene expression quantification, normalization and differential analysis (with thorough correction for confounders) revealed genes associated to PTSD; LRP8 and GOLM1 These preliminary results provide a proof-of-principle for the diagnostic utility of blood-based gene expression profiles for tracking symptoms of post-traumatic stress disorder in soldiers returning from tour. It is also the first to report transcriptome-wide expression profiles alongside a post-traumatic symptom checklist.


Assuntos
Militares , Transtornos de Estresse Pós-Traumáticos/genética , Transcriptoma , Adulto , Biomarcadores/sangue , Perfilação da Expressão Gênica/métodos , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , RNA Mensageiro/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transtornos de Estresse Pós-Traumáticos/sangue
9.
Cell Mol Life Sci ; 76(1): 163-178, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30327840

RESUMO

Low-density lipoprotein receptor-related protein 4 (LRP4) is a multi-functional protein implicated in bone, kidney and neurological diseases including Cenani-Lenz syndactyly (CLS), sclerosteosis, osteoporosis, congenital myasthenic syndrome and myasthenia gravis. Why different LRP4 mutation alleles cause distinct and even contrasting disease phenotypes remain unclear. Herein, we utilized the zebrafish model to search for pathways affected by a deficiency of LRP4. The lrp4 knockdown in zebrafish embryos exhibits cyst formations at fin structures and the caudal vein plexus, malformed pectoral fins, defective bone formation and compromised kidney morphogenesis; which partially phenocopied the human LRP4 mutations and were reminiscent of phenotypes resulting form a perturbed Notch signaling pathway. We discovered that the Lrp4-deficient zebrafish manifested increased Notch outputs in addition to enhanced Wnt signaling, with the expression of Notch ligand jagged1b being significantly elevated at the fin structures. To examine conservatism of signaling mechanisms, the effect of LRP4 missense mutations and siRNA knockdowns, including a novel missense mutation c.1117C > T (p.R373W) of LRP4, were tested in mammalian kidney and osteoblast cells. The results showed that LRP4 suppressed both Wnt/ß-Catenin and Notch signaling pathways, and these activities were perturbed either by LRP4 missense mutations or by a knockdown of LRP4. Our finding underscore that LRP4 is required for limiting Jagged-Notch signaling throughout the fin/limb and kidney development, whose perturbation representing a novel mechanism for LRP4-related diseases. Moreover, our study reveals an evolutionarily conserved relationship between LRP4 and Jagged-Notch signaling, which may shed light on how the Notch signaling is fine-tuned during fin/limb development.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas Relacionadas a Receptor de LDL/genética , Receptores Notch/metabolismo , Proteínas Serrate-Jagged/metabolismo , Transdução de Sinais , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Nadadeiras de Animais/embriologia , Nadadeiras de Animais/metabolismo , Animais , Extremidades/embriologia , Extremidades/fisiologia , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Rim/embriologia , Rim/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Mutação , Mutação de Sentido Incorreto , Organogênese , Via de Sinalização Wnt , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
10.
Int J Mol Sci ; 19(11)2018 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-30373276

RESUMO

The ATP-binding cassette transporter member A1 (ABCA1) and apolipoprotein E (ApoE) are major cholesterol transporters that play important roles in cholesterol homeostasis in the brain. Previous research demonstrated that specific deletion of brain-ABCA1 (ABCA1-B/-B) reduced brain grey matter (GM) and white matter (WM) density in the ischemic brain and decreased functional outcomes after stroke. However, the downstream molecular mechanism underlying brain ABCA1-deficiency-induced deficits after stroke is not fully understood. Adult male ABCA1-B/-B and ABCA1-floxed control mice were subjected to distal middle-cerebral artery occlusion and were intraventricularly infused with artificial mouse cerebrospinal fluid as vehicle control or recombinant human ApoE2 into the ischemic brain starting 24 h after stroke for 14 days. The ApoE/apolipoprotein E receptor 2 (ApoER2)/high-density lipoprotein (HDL) levels and GM/WM remodeling and functional outcome were measured. Although ApoE2 increased brain ApoE/HDL levels and GM/WM density, negligible functional improvement was observed in ABCA1-floxed-stroke mice. ApoE2-administered ABCA1-B/-B stroke mice exhibited elevated levels of brain ApoE/ApoER2/HDL, increased GM/WM density, and neurogenesis in both the ischemic ipsilateral and contralateral brain, as well as improved neurological function compared with the vehicle-control ABCA1-B/-B stroke mice 14 days after stroke. Ischemic lesion volume was not significantly different between the two groups. In vitro supplementation of ApoE2 into primary cortical neurons and primary oligodendrocyte-progenitor cells (OPCs) significantly increased ApoER2 expression and enhanced cholesterol uptake. ApoE2 promoted neurite outgrowth after oxygen-glucose deprivation and axonal outgrowth of neurons, and increased proliferation/survival of OPCs derived from ABCA1-B/-B mice. Our data indicate that administration of ApoE2 minimizes the adverse effects of ABCA1 deficiency after stroke, at least partially by promoting cholesterol traffic/redistribution and GM/WM remodeling via increasing the ApoE/HDL/ApoER2 signaling pathway.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/deficiência , Apolipoproteínas E/farmacologia , Acidente Vascular Cerebral/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Apolipoproteínas E/administração & dosagem , Apolipoproteínas E/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , HDL-Colesterol/metabolismo , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico
11.
Int J Mol Sci ; 19(10)2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30304853

RESUMO

Apolipoprotein E receptor 2 (ApoER2) and VLDL receptor belong to the low density lipoprotein receptor family and bind apolipoprotein E. These receptors interact with the clathrin machinery to mediate endocytosis of macromolecules but also interact with other adapter proteins to perform as signal transduction receptors. The best characterized signaling pathway in which ApoER2 and VLDL receptor (VLDLR) are involved is the Reelin pathway. This pathway plays a pivotal role in the development of laminated structures of the brain and in synaptic plasticity of the adult brain. Since Reelin and apolipoprotein E, are ligands of ApoER2 and VLDLR, these receptors are of interest with respect to Alzheimer's disease. We will focus this review on the complex structure of ApoER2 and VLDLR and a recently characterized ligand, namely clusterin.


Assuntos
Proteínas Relacionadas a Receptor de LDL/metabolismo , Receptores de LDL/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Clusterina/genética , Clusterina/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Expressão Gênica , Humanos , Proteínas Relacionadas a Receptor de LDL/química , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica , Receptores de LDL/química , Receptores de LDL/genética , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Relação Estrutura-Atividade
12.
Cancer Lett ; 438: 165-173, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30227220

RESUMO

Triple-negative breast cancer (TNBC) is the most difficult subtype of breast cancer to treat due to a paucity of effective targeted therapies. Many studies have reported that breast cancer stem cells (BCSCs) are enriched in TNBC and are responsible for chemoresistance and metastasis. In this study, we identify LRP8 as a novel positive regulator of BCSCs in TNBC. LRP8 is highly expressed in TNBC compared to other breast cancer subtypes and its genomic locus is amplified in 24% of TNBC tumors. Knockdown of LRP8 in TNBC cell lines inhibits Wnt/ß-catenin signaling, decreases BCSCs, and suppresses tumorigenic potential in xenograft models. LRP8 knockdown also induces a more differentiated, luminal-epithelial phenotype and thus sensitizes the TNBC cells to chemotherapy. Together, our study highlights LRP8 as a novel therapeutic target for TNBC as inhibition of LRP8 can attenuate Wnt/ß-catenin signaling to suppress BCSCs.


Assuntos
Neoplasias da Mama/genética , Proteínas Relacionadas a Receptor de LDL/genética , Células-Tronco Neoplásicas/metabolismo , Interferência de RNA , Neoplasias de Mama Triplo Negativas/genética , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Proteínas Relacionadas a Receptor de LDL/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Terapêutica com RNAi/métodos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/terapia , Carga Tumoral/genética , Via de Sinalização Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , beta Catenina/genética
13.
Stem Cell Res ; 31: 127-130, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30077089

RESUMO

A 87-year old Alzheimer's Disease(AD) male patient donated his Peripheral blood mononuclear cells (PBMC). The non-integrating episomal vector system was used to reprogram PBMCs with the human OKSM transcription factors. The pluripotency of transgene-free iPSCs was confirmed by immunocytochemistry for pluripotency markers and by the ability of the iPSCs to differentiate spontaneously into 3 germ layers in vitro. In addition, the iPSC line displayed a normal karyotype. Our model might offer a good platform to further study the pathological mechanisms, to identify early biomarkers, and also for drug testing studies in AD.


Assuntos
Doença de Alzheimer/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Grupo com Ancestrais do Continente Asiático , Diferenciação Celular , Humanos , Masculino , Mutação
14.
Bone ; 116: 321-332, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30077757

RESUMO

Sclerosteosis (SOST) refers to two extremely rare yet similar skeletal dysplasias featuring a diffusely radiodense skeleton together with congenital syndactyly. SOST1 is transmitted as an autosomal recessive (AR) trait and to date caused by ten homozygous loss-of-function mutations within the gene SOST that encodes the inhibitor of Wnt-mediated bone formation, sclerostin. SOST2 is transmitted as an autosomal dominant (AD) or AR trait and to date caused by one heterozygous or two homozygous loss-of-function mutation(s), respectively, within the gene LRP4 that encodes the sclerostin interaction protein, low-density lipoprotein receptor-related protein 4 (LRP4). Herein, we investigated two teenagers and one middle-aged man with SOST in three families living in the state of Tamil Nadu in southern India. Next generation sequencing of their genomic DNA using our high bone density gene panel revealed SOST1 in the teenagers caused by a unique homozygous nonsense SOST mutation (c.129C > G, p.Tyr43X) and SOST2 in the man caused by homozygosity for one of the two known homozygous missense LRP4 mutations (c.3508C > T, p.Arg1170Trp). He becomes the fourth individual and the first non-European recognized with SOST2. His clinical course was milder than the life-threatening SOST1 demonstrated by the teenagers who suffered blindness, deafness, and raised intracranial pressure, yet his congenital syndactyly was more striking by featuring bony fusion of digits. All three patients were from consanguineous families and heterozygosity for the SOST mutation was documented in the mothers of both teenagers. Thus, on the endogamous genetic background of Indian Tamils, SOST1 from sclerostin deficiency compared to SOST2 from LRP4 deactivation is a more severe and life-threatening disorder featuring complications due to osteosclerosis of especially the skull. In contrast, the syndactyly of SOST2 is particularly striking by involving bony fusion of some digits. Both the SOST and LRP4 mutations in this ethnic population likely reflect genetic founders.


Assuntos
Hiperostose/patologia , Sindactilia/patologia , Adolescente , Sequência de Bases , Proteínas Morfogenéticas Ósseas/genética , Osso e Ossos/metabolismo , Análise Mutacional de DNA , Família , Feminino , Marcadores Genéticos/genética , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/genética , Índia , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Pessoa de Meia-Idade , Minerais/metabolismo , Linhagem , Sindactilia/diagnóstico por imagem , Sindactilia/genética
15.
Neurobiol Aging ; 71: 266.e11-266.e24, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30078640

RESUMO

SORL1 encodes a 250-kDa protein named sorLA, a functional sorting receptor for the amyloid precursor protein (APP). Several single nucleotide polymorphisms of the gene SORL1, encoding sorLA, are genetically associated with Alzheimer's disease (AD). In the existing literature, SORL1 is insufficiently described at the transcriptional level, and there is very limited amount of functional data defining different transcripts. We have characterized a SORL1 transcript containing a novel exon 30B. The transcript is expressed in most brain regions with highest expression in the temporal lobe and hippocampus. Exon 30B is spliced to exon 31, leading to a mature transcript that encodes an 829 amino acid sorLA receptor. This receptor variant lacks the binding site for APP and is unlikely to function in APP sorting. This transcript is expressed in equal amounts in the cerebellum from AD and non-AD individuals. Our data describe a transcript that encodes a truncated sorLA receptor, suggesting novel neuronal functions for sorLA and that alternative transcription provides a mechanism for SORL1 activity regulation.


Assuntos
Doença de Alzheimer/genética , Encéfalo/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Idoso , Doença de Alzheimer/metabolismo , Linhagem Celular , Éxons , Feminino , Predisposição Genética para Doença , Humanos , Proteínas Relacionadas a Receptor de LDL/metabolismo , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Neurônios/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sequência de DNA
16.
Int J Mol Sci ; 19(8)2018 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-30081553

RESUMO

Pulmonary arterial hypertension (PAH) is characterized by occlusion of lung arterioles, leading to marked increases in pulmonary vascular resistance. Although heritable forms of PAH are known to be driven by genetic mutations that share some commonality of function, the extent to which these effectors converge to regulate shared processes in this disease is unknown. We have causally connected extracellular matrix (ECM) remodeling and mechanotransduction to the miR-130/301 family in a feedback loop that drives vascular activation and downstream PAH. However, the molecular interconnections between factors genetically associated with PAH and this mechano-driven feedback loop remain undefined. We performed systematic manipulation of matrix stiffness, the miR-130/301 family, and factors genetically associated with PAH in primary human pulmonary arterial cells and assessed downstream and reciprocal consequences on their expression. We found that a network of factors linked to heritable PAH converges upon the matrix stiffening-miR-130/301-PPARγ-LRP8 axis in order to remodel the ECM. Furthermore, we leveraged a computational network biology approach to predict a number of additional molecular circuits functionally linking this axis to the ECM. These results demonstrate that multiple genes associated with heritable PAH converge to control the miR-130/301 circuit, triggering a self-amplifying feedback process central to pulmonary vascular stiffening and disease.


Assuntos
Matriz Extracelular/metabolismo , Hipertensão Pulmonar/metabolismo , MicroRNAs/metabolismo , Células Cultivadas , Predisposição Genética para Doença/genética , Humanos , Hipertensão Pulmonar/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Mecanotransdução Celular/fisiologia , MicroRNAs/genética , MicroRNAs/fisiologia , PPAR gama/genética , PPAR gama/metabolismo , Artéria Pulmonar/citologia , Artéria Pulmonar/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Int J Mol Med ; 42(4): 2098-2106, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30066942

RESUMO

The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) protects a variety of cell types against neuronal apoptosis by binding to apolipoprotein E receptor 2 (ApoER2). The present study aimed to determine the association between PCSK9/ApoER2 signaling and neuronal apoptosis following middle cerebral artery occlusion (MCAO) injury in hyperlipidemic mice. For this purpose, C57BL/6 mice fed with a high­fat diet (HFD) for 6 weeks were exposed to MCAO. Subsequently, PCSK9 was inhibited by a lentiviral vector harboring short­hairpin RNA (shRNA) targeting PCSK9, which was stereotaxically injected into the cerebral cortex of mice. At 48 h post­ischemia, hematoxylin­eosin staining and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay were performed to determine cerebral tissue injury and apoptosis. PCSK9 and ApoER2 expression levels were assessed by reverse transcription­quantitative polymerase chain reaction, immunohistochemistry and western blotting. The results indicated that hyperlipidemia and increased PCSK9 expression were evident in HFD mice. Cerebral histological injury and neuronal apoptosis, as well as PCSK9 and ApoER2 levels, which were increased upon ischemia in hyperlipidemic mice, were attenuated by PCSK9 shRNA treatment. These protective effects of PCSK9 shRNA interference were associated with decreased neuronal apoptosis and a reduced level of ApoER2 expression in the hippocampus and cortex. The data of the present study demonstrated that the PCSK9 shRNA­mediated anti­apoptotic effect induced by MCAO in hyperlipidemic mice is associated with ApoER2 downregulation, which may be a potential new therapy for stroke treatment in patients with hyperlipidemia.


Assuntos
Apoptose , Isquemia Encefálica/metabolismo , Regulação para Baixo , Hiperlipidemias/metabolismo , Proteínas Relacionadas a Receptor de LDL/biossíntese , Pró-Proteína Convertase 9/biossíntese , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Hiperlipidemias/genética , Hiperlipidemias/patologia , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Camundongos , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
18.
Science ; 361(6404)2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30139844

RESUMO

The architecture of the neurovascular unit (NVU) is controlled by the communication of neurons, glia, and vascular cells. We found that the neuronal guidance cue reelin possesses proangiogenic activities that ensure the communication of endothelial cells (ECs) with the glia to control neuronal migration and the establishment of the blood-brain barrier in the mouse brain. Apolipoprotein E receptor 2 (ApoER2) and Disabled1 (Dab1) expressed in ECs are required for vascularization of the retina and the cerebral cortex. Deletion of Dab1 in ECs leads to a reduced secretion of laminin-α4 and decreased activation of integrin-ß1 in glial cells, which in turn control neuronal migration and barrier properties of the NVU. Thus, reelin signaling in the endothelium is an instructive and integrative cue essential for neuro-glia-vascular communication.


Assuntos
Comunicação Celular , Córtex Cerebral/irrigação sanguínea , Endotélio Vascular/fisiologia , Neovascularização Fisiológica , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/fisiologia , Neurônios/fisiologia , Vasos Retinianos/fisiologia , Animais , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/fisiologia , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Movimento Celular , Endotélio Vascular/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Deleção de Genes , Integrina beta1/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Laminina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/metabolismo , Vasos Retinianos/citologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transdução de Sinais
19.
Lancet Neurol ; 17(7): 597-608, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29887161

RESUMO

BACKGROUND: Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders. METHODS: Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies from centres in Portugal, Sardinia, and Taiwan, and screened them for specific variants. We also did mRNA and brain pathology studies in three patients from the international multicentre series carrying disease-associated variants, and we did functional protein studies in in-vitro models, including neurons from induced pluripotent stem-like cells. FINDINGS: Molecular studies were done between Jan 1, 2008, and Dec 31, 2017. In the initial kindred of ten affected Italian individuals (mean age of disease onset 59·8 years [SD 8·7]), we detected significant linkage of Parkinson's disease to chromosome 14 and nominated LRP10 as the disease-causing gene. Among the international series of 660 probands, we identified eight individuals (four with Parkinson's disease, two with Parkinson's disease dementia, and two with dementia with Lewy bodies) who carried different, rare, potentially pathogenic LRP10 variants; one carrier was found among 645 controls with abdominal aortic aneurysms. In the independent series, two of these eight variants were detected in three additional Parkinson's disease probands (two from Sardinia and one from Taiwan) but in none of the controls. Of the 11 probands from the international and independent cohorts with LRP10 variants, ten had a positive family history of disease and DNA was available from ten affected relatives (in seven of these families). The LRP10 variants were present in nine of these ten relatives, providing independent-albeit limited-evidence of co-segregation with disease. Post-mortem studies in three patients carrying distinct LRP10 variants showed severe Lewy body pathology. Of nine variants identified in total (one in the initial family and eight in stage 2), three severely affected LRP10 expression and mRNA stability (1424+5delG, 1424+5G→A, and Ala212Serfs*17, shown by cDNA analysis), four affected protein stability (Tyr307Asn, Gly603Arg, Arg235Cys, and Pro699Ser, shown by cycloheximide-chase experiments), and two affected protein localisation (Asn517del and Arg533Leu; shown by immunocytochemistry), pointing to loss of LRP10 function as a common pathogenic mechanism. INTERPRETATION: Our findings implicate LRP10 gene defects in the development of inherited forms of α-synucleinopathies. Future elucidation of the function of the LRP10 protein and pathways could offer novel insights into mechanisms, biomarkers, and therapeutic targets. FUNDING: Stichting ParkinsonFonds, Dorpmans-Wigmans Stichting, Erasmus Medical Center, ZonMw-Memorabel programme, EU Joint Programme Neurodegenerative Disease Research (JPND), Parkinson's UK, Avtal om Läkarutbildning och Forskning (ALF) and Parkinsonfonden (Sweden), Lijf and Leven foundation, and cross-border grant of Alzheimer Netherlands-Ligue Européene Contre la Maladie d'Alzheimer (LECMA).


Assuntos
Proteínas Relacionadas a Receptor de LDL/genética , Doença por Corpos de Lewy/genética , Doença de Parkinson/genética , Encéfalo/patologia , Cromossomos Humanos Par 14/genética , Demência/epidemiologia , Demência/etiologia , Demência/genética , Família , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Itália , Doença por Corpos de Lewy/epidemiologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/epidemiologia , Linhagem , Células-Tronco Pluripotentes/metabolismo , RNA Mensageiro/química , RNA Mensageiro/genética
20.
J Alzheimers Dis ; 64(2): 459-471, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29865048

RESUMO

Alzheimer's disease (AD) is characterized by memory loss and executive dysfunction, which correspond to structural changes to the medial temporal lobes (MTL) and prefrontal cortex (PFC), respectively. Given the overlap in cognitive deficits between healthy aging and the earliest stages of AD, early detection of AD remains a challenge. The goal of the present study was to study MTL- and PFC-dependent cognitive functioning in middle-aged individuals at genetic risk for AD or cognitive impairment who do not currently manifest any clinical symptoms. Participants (N = 150; aged 40-60 years) underwent genotyping of 47 single nucleotide polymorphisms (SNPs) in six genes previously associated with memory or executive functioning: APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT. They completed two MTL-dependent tasks, the virtual Morris Water Task (vMWT) and transverse patterning discriminations task (TPDT), and the PFC-dependent reversal learning task. Although age was associated with poorer performance on the vMWT and TPDT within this middle-aged sample, there were no genotype-associated differences in cognitive performance. Although the vMWT and TPDT may be sensitive to age-related changes in cognition, carriers of APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT risk alleles do not exhibit alteration in MTL- and PFC-dependent functioning in middle age compared to non-carriers.


Assuntos
Envelhecimento , Disfunção Cognitiva/genética , Função Executiva/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Adulto , Análise de Variância , Apolipoproteínas E/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Catecol O-Metiltransferase/genética , Feminino , Genótipo , Humanos , Vida Independente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Aprendizagem em Labirinto , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Fosfoproteínas/genética , Tempo de Reação/fisiologia , Interface Usuário-Computador
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