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1.
Stem Cell Res ; 56: 102558, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34626895

RESUMO

Reproducibility of expression patterns in iPSC-derived cells from different labs is an important first step in ensuring replication of biochemical or functional assays that are performed in different labs. Here we show that reproducible gene expression patterns from iPSCs and iPSC-derived neurons matured and collected at two separate laboratory locations can be achieved by closely matching protocols and reagents. While there are significant differences in gene expression between iPSCs and differentiated neurons, as well as between different donor lines of the same cell type, transcriptional changes that vary with laboratory sites are relatively small. These results suggest that making great efforts to match protocols, reagents and technical methods between labs may improve the reproducibility of iPSC-derived cell models.


Assuntos
Células-Tronco Pluripotentes Induzidas , Diferenciação Celular , Expressão Gênica , Neurônios , Reprodutibilidade dos Testes
2.
Proc Natl Acad Sci U S A ; 118(31)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34312226

RESUMO

Mechanisms controlling myelination during central nervous system (CNS) maturation play a pivotal role in the development and refinement of CNS circuits. The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oligodendrocyte lineage. Here, we demonstrate that THAP1 modulates the extracellular matrix (ECM) composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs). Thap1 -/- OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an autoinhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding ß-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing ß-glucuronidase rescues Thap1 -/- OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development.

3.
Front Neural Circuits ; 15: 644776, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079441

RESUMO

Dopamine is an important chemical messenger in the brain, which modulates movement, reward, motivation, and memory. Different populations of neurons can produce and release dopamine in the brain and regulate different behaviors. Here we focus our discussion on a small but distinct group of dopamine-producing neurons, which display the most profound loss in the ventral substantia nigra pas compacta of patients with Parkinson's disease. This group of dopaminergic neurons can be readily identified by a selective expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and accounts for 70% of total nigrostriatal dopaminergic neurons in both human and mouse brains. Recently, we presented the first whole-brain circuit map of these ALDH1A1-positive dopaminergic neurons and reveal an essential physiological function of these neurons in regulating the vigor of movement during the acquisition of motor skills. In this review, we first summarize previous findings of ALDH1A1-positive nigrostriatal dopaminergic neurons and their connectivity and functionality, and then provide perspectives on how the activity of ALDH1A1-positive nigrostriatal dopaminergic neurons is regulated through integrating diverse presynaptic inputs and its implications for potential Parkinson's disease treatment.

4.
Sci Rep ; 11(1): 6353, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737586

RESUMO

Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. We identified a nonsense mutation in SORL1 VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation in CLCN6 (p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in the CSF1R Tyrosin kinase flanking regions (p.E573K and p.R549H). By contrast, only a minority of patients carried pathogenic C9orf72 repeat expansions (1%) and likely moderately pathogenic variants in GRN (p.C105Y, p.C389fs and p.C139R) (3%). In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments.


Assuntos
Canais de Cloreto/genética , Demência Frontotemporal/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Lipofuscinoses Ceroides Neuronais/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adulto , Idoso , Afasia/epidemiologia , Afasia/genética , Afasia/patologia , Feminino , Demência Frontotemporal/epidemiologia , Demência Frontotemporal/patologia , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Lipofuscinoses Ceroides Neuronais/epidemiologia , Lipofuscinoses Ceroides Neuronais/patologia , Fenótipo
5.
Front Chem ; 9: 643411, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777903

RESUMO

Massive hemorrhage caused by the uncontrolled release of thrombolysis drugs is a key issue of thrombolysis therapy in clinical practice. In this study, we report a near-infrared (NIR) light-triggered drug delivery system, i.e., CuS@mSiO2-PEG (CSP) nanoparticles, for the loading of a thrombolytic drug (urokinase plasminogen activators, uPA). CSP nanoparticles with the CuS nanoparticles as photothermal agents and mesoporous SiO2 for the loading of uPA were synthesized using a facile hydrothermal method. The CSP core-shell nanoparticles were demonstrated to possess excellent photothermal performance, exhibiting a photothermal conversion efficiency of up to 52.8%. Due to the mesoporous SiO2 coating, the CSP core-shell nanoparticles exhibited appropriate pore size, high pore volume, and large surface area; thus, they showed great potential to be used as drug carriers. Importantly, the release of uPA from CuS@mSiO2-PEG/uPA (CSPA) carriers can be promoted by the NIR laser irradiation. The drug loading content of uPA for the as-prepared NIR-triggered drug delivery system was calculated to be 8.2%, and the loading efficiency can be determined to be as high as 89.6%. Due to the excellent photothermal effect of CSP nanocarriers, the NIR-triggered drug delivery system can be used for infrared thermal imaging in vivo. The in vivo thrombolysis assessment demonstrated that the NIR-triggered drug delivery system showed excellent thrombolytic ability under the irradiation of an 808 nm laser, showing the combined therapy for thrombolysis. As far as we know, the CSPA core-shell nanoparticles used as NIR-triggered drug delivery systems for thrombolysis have not been reported.

6.
J Parkinsons Dis ; 11(2): 569-584, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33523017

RESUMO

BACKGROUND: Coding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson's disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, suggesting that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. OBJECTIVE: Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, we set out to determine whether there are any consequences on brain function with aging after deletion of both genes. METHODS: We generated a double knockout mouse model and performed a battery of motor and non-motor behavioral tests. We then investigated postmortem assays to determine the presence of PD-like pathology, including nigral dopamine cell count, astrogliosis, microgliosis, and striatal monoamine content. RESULTS: Behaviorally, we noted only that 18-24-month Rab29-/- and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in the outcomes that represented PD-like pathology. CONCLUSION: These results suggest that depletion of both LRRK2 and RAB29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.

7.
Nat Genet ; 53(3): 294-303, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33589841

RESUMO

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.


Assuntos
Estudo de Associação Genômica Ampla , Doença por Corpos de Lewy/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Estudos de Casos e Controles , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Glucosilceramidase/genética , Humanos , Proteínas Nucleares/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras de Tumor/genética , alfa-Sinucleína/genética
8.
Mov Disord ; 36(5): 1250-1258, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33497488

RESUMO

BACKGROUND: Parkinson's disease (PD) is a genetically complex neurodegenerative disease with ~20 genes known to contain mutations that cause PD or atypical parkinsonism. Large-scale next-generation sequencing projects have revolutionized genomics research. Applying these data to PD, many genes have been reported to contain putative disease-causing mutations. In most instances, however, the results remain quite limited and rather preliminary. Our aim was to assist researchers on their search for PD-risk genes and variant candidates with an easily accessible and open summary-level genomic data browser for the PD research community. METHODS: Sequencing and imputed genotype data were obtained from multiple sources and harmonized and aggregated. RESULTS: In total we included a total of 102,127 participants, including 28,453 PD cases, 1650 proxy cases, and 72,024 controls. CONCLUSIONS: We present here the Parkinson's Disease Sequencing Browser: a Shiny-based web application that presents comprehensive summary-level frequency data from multiple large-scale genotyping and sequencing projects https://pdgenetics.shinyapps.io/VariantBrowser/. Published © 2021 This article is a U.S. Government work and is in the public domain in the USA. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Transtornos Parkinsonianos , DNA , Humanos , Mutação/genética , Doença de Parkinson/genética
9.
Mov Disord ; 36(2): 449-459, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33107653

RESUMO

BACKGROUND: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci. METHODS: Genome-wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross-trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild-type mice. Genetic variability of candidate genes was further investigated using independent whole-exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls. RESULTS: We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild-type mice and had elevated burden of protein-coding variants in independent MSA and inflammatory bowel disease cohorts. CONCLUSION: Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doenças Inflamatórias Intestinais , Atrofia de Múltiplos Sistemas , Animais , Estudo de Associação Genômica Ampla , Humanos , Doenças Inflamatórias Intestinais/genética , Camundongos , Camundongos Transgênicos , Atrofia de Múltiplos Sistemas/genética , alfa-Sinucleína/genética
10.
Neuron ; 109(3): 448-460.e4, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33242422

RESUMO

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.


Assuntos
Esclerose Amiotrófica Lateral/genética , Expansão das Repetições de DNA , Demência Frontotemporal/genética , Proteína Huntingtina/genética , Esclerose Amiotrófica Lateral/patologia , Demência Frontotemporal/patologia , Humanos , Mutação , Sequenciamento Completo do Genoma
11.
Neurology ; 96(4): e600-e609, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33208543

RESUMO

OBJECTIVE: To assess the burden of rare genetic variants and to estimate the contribution of known amyotrophic lateral sclerosis (ALS) genes in an Italian population-based cohort, we performed whole genome sequencing in 959 patients with ALS and 677 matched healthy controls. METHODS: We performed genome sequencing in a population-based cohort (Piemonte and Valle d'Aosta Registry for ALS [PARALS]). A panel of 40 ALS genes was analyzed to identify potential disease-causing genetic variants and to evaluate the gene-wide burden of rare variants among our population. RESULTS: A total of 959 patients with ALS were compared with 677 healthy controls from the same geographical area. Gene-wide association tests demonstrated a strong association with SOD1, whose rare variants are the second most common cause of disease after C9orf72 expansion. A lower signal was observed for TARDBP, proving that its effect on our cohort is driven by a few known causal variants. We detected rare variants in other known ALS genes that did not surpass statistical significance in gene-wise tests, thus highlighting that their contribution to disease risk in our cohort is limited. CONCLUSIONS: We identified potential disease-causing variants in 11.9% of our patients. We identified the genes most frequently involved in our cohort and confirmed the contribution of rare variants in disease risk. Our results provide further insight into the pathologic mechanism of the disease and demonstrate the importance of genome-wide sequencing as a diagnostic tool.


Assuntos
Esclerose Amiotrófica Lateral/epidemiologia , Esclerose Amiotrófica Lateral/genética , Análise Mutacional de DNA/métodos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Vigilância da População , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/diagnóstico , Proteína C9orf72/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
FASEB J ; 34(9): 12239-12254, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33000527

RESUMO

α-Synuclein (α-syn)-induced neurotoxicity has been generally accepted as a key step in the pathogenesis of Parkinson's disease (PD). Microtubule-associated protein tau, which is considered second only to α-syn, has been repeatedly linked with PD in association studies. However, the underlying interaction between these two PD-related proteins in vivo remains unclear. To investigate how the expression of tau affects α-syn-induced neurodegeneration in vivo, we generated triple transgenic mice that overexpressed α-syn A53T mutation in the midbrain dopaminergic neurons (mDANs) with different expression levels of tau. Here, we found that tau had no significant effect on the A53T α-syn-mediated mDANs degeneration. However, tau knockout could modestly promote the formation of α-syn aggregates, accelerate the severe and progressive degeneration of parvalbumin-positive (PV+) neurons in substantia nigra pars reticulata (SNR), accompanied with anxiety-like behavior in aged PD-related α-syn A53T mice. The mechanisms may be associated with A53T α-syn-mediated specifically successive impairment of N-methyl-d-aspartate receptor subunit 2B (NR2B), postsynaptic density-95 (PSD-95) and microtubule-associated protein 1A (MAP1A) in PV+ neurons. Our study indicates that MAP1A may play a beneficial role in preserving the survival of PV+ neurons, and that inhibition of the impairment of NR2B/PSD-95/MAP1A pathway, may be a novel and preferential option to ameliorate α-syn-induced neurodegeneration.


Assuntos
Mutação , Degeneração Neural , Doença de Parkinson/etiologia , Parvalbuminas/análise , Substância Negra/patologia , alfa-Sinucleína/genética , Proteínas tau/fisiologia , Animais , Proteína 4 Homóloga a Disks-Large/fisiologia , Proteínas de Homeodomínio/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/fisiologia , Doença de Parkinson/patologia , Fragmentos de Peptídeos/fisiologia , Agregados Proteicos , Receptores de N-Metil-D-Aspartato/fisiologia , Fatores de Transcrição/fisiologia , alfa-Sinucleína/fisiologia , Proteínas tau/química , Proteínas tau/genética
16.
Mol Neurodegener ; 15(1): 12, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075681

RESUMO

BACKGROUND: Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with familial forms of late onset Parkinson's disease (PD), the most common age-related movement disorder. The dysfunction of dopamine transmission contributes to PD-related motor symptoms. Interestingly, LRRK2 is more abundant in the dopaminoceptive striatal spiny projection neurons (SPNs) compared to the dopamine-producing nigrostriatal dopaminergic neurons. Aging is the most important risk factor for PD and other neurodegenerative diseases. However, whether LRRK2 modulates the aging of SPNs remains to be determined. METHODS: We conducted RNA-sequencing (RNA-seq) analyses of striatal tissues isolated from Lrrk2 knockout (Lrrk2-/-) and control (Lrrk2+/+) mice at 2 and 12 months of age. We examined SPN nuclear DNA damage and epigenetic modifications; SPN nuclear, cell body and dendritic morphology; and the locomotion and motor skill learning of Lrrk2+/+ and Lrrk2-/- mice from 2 to 24 months of age. Considering the strength of cell cultures for future mechanistic studies, we also performed preliminary studies in primary cultured SPNs derived from the Lrrk2+/+ and Lrrk2-/- mice as well as the PD-related Lrrk2 G2019S and R1441C mutant mice. RESULTS: Lrrk2-deficiency accelerated nuclear hypertrophy and induced dendritic atrophy, soma hypertrophy and nuclear invagination in SPNs during aging. Additionally, increased nuclear DNA damage and abnormal histone methylations were also observed in aged Lrrk2-/- striatal neurons, together with alterations of molecular pathways involved in regulating neuronal excitability, genome stability and protein homeostasis. Furthermore, both the PD-related Lrrk2 G2019S mutant and LRRK2 kinase inhibitors caused nuclear hypertrophy, while the Lrrk2 R1441C mutant and γ-Aminobutyric acid type A receptor (GABA-AR) inhibitors promoted nuclear invagination in the cultured SPNs. On the other hand, inhibition of neuron excitability prevented the formation of nuclear invagination in the cultured Lrrk2-/- and R1441C SPNs. CONCLUSIONS: Our findings support an important physiological function of LRRK2 in maintaining nuclear structure integrity and genomic stability during the normal aging process, suggesting that PD-related LRRK2 mutations may cause the deterioration of neuronal structures through accelerating the aging process.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Animais , Núcleo Celular/patologia , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Instabilidade Genômica/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
18.
Neurol Genet ; 5(4): e347, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31404212

RESUMO

Objective: Patients with corticobasal syndrome (CBS) present with heterogeneous clinical features, including asymmetric parkinsonism, dyspraxia, aphasia, and cognitive impairment; to better understand the genetic etiology of this rare disease, we undertook a genetic analysis of microtubule-associated protein tau (MAPT). Methods: We performed a genetic evaluation of MAPT mutations in 826 neurologically healthy controls and 173 cases with CBS using the Illumina NeuroChip genotyping array. Results: We identified 2 patients with CBS heterozygous for a rare mutation in MAPT (p.V363I) that is located in the highly conserved microtubule-binding domain. One patient was pathologically confirmed and demonstrated extensive 4-repeat-tau-positive thread pathology, achromatic neurons, and astrocytic plaques consistent with corticobasal degeneration (CBD). Conclusions: We report 2 CBS cases carrying the rare p.V363I MAPT mutation, one of which was pathologically confirmed as CBD. Our findings support the notion that this rare coding change is pathogenic.

19.
Cell Rep ; 28(5): 1167-1181.e7, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31365862

RESUMO

Parkinson's disease causes the most profound loss of the aldehyde dehydrogenase 1A1-positive (ALDH1A1+) nigrostriatal dopaminergic neuron (nDAN) subpopulation. The connectivity and functionality of ALDH1A1+ nDANs, however, remain poorly understood. Here, we show in rodent brains that ALDH1A1+ nDANs project predominantly to the rostral dorsal striatum, from which they also receive most monosynaptic inputs, indicating extensive reciprocal innervations with the striatal spiny projection neurons (SPNs). Functionally, genetic ablation of ALDH1A1+ nDANs causes severe impairments in motor skill learning, along with a reduction in high-speed walking. While dopamine replacement therapy accelerated walking speed, it failed to improve motor skill learning in ALDH1A1+ nDAN-ablated mice. Altogether, our study provides a comprehensive whole-brain connectivity map and reveals a key physiological function of ALDH1A1+ nDANs in motor skill acquisition, suggesting the motor learning processes require ALDH1A1+ nDANs to integrate diverse presynaptic inputs and supply dopamine with dynamic precision.


Assuntos
Família Aldeído Desidrogenase 1/metabolismo , Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/metabolismo , Aprendizagem , Retinal Desidrogenase/metabolismo , Substância Negra/metabolismo , Família Aldeído Desidrogenase 1/genética , Animais , Corpo Estriado/citologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Camundongos , Camundongos Transgênicos , Retinal Desidrogenase/genética
20.
Ann Diagn Pathol ; 42: 59-63, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31310900

RESUMO

Although several lines of evidence existed suggesting that Mortalin was linked with survival in malignant tumors; it has been barely described regarding the prognostic involvement of its expression in hepatocellular carcinoma (HCC). Herein, to understand the prognostic meaning of Mortalin expression, Immunohistochemistry was undertaken to observe the immunohistochemical characteristics of Mortalin on HCC tissue microarray consisting of 90 cases of HCC and its paired normal control dots, followed by detailed statistical analysis with the accompanying clinicopathological variables available, including gender, age, tumor size, differentiation, cirrhosis, vascular invasion, clinical stage, T classification and intrahepatic metastases. Meanwhile, Kaplan-Meier survival curve was plotted to analyze the prognostic difference for patients with high and low expression of Mortalin. It was exhibited that Mortalin was over-expressed in HCC tissues relative to paired normal control and elevated Mortalin significantly correlated with vascular invasion, clinical stage and intrahepatic metastasis. Kaplan-Meier survival analysis revealed that Mortalin was remarkably associated with overall survival and disease-free survival. Multivariate Cox regression analysis showed that expression of Mortalin was an independent prognostic factor in HCC. Collectively, the data we provided here support the prognostic prediction value of Mortalin in HCC.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/patologia , Proteínas de Choque Térmico HSP70/biossíntese , Neoplasias Hepáticas/patologia , Proteínas Mitocondriais/biossíntese , Adulto , Idoso , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico
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