Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros

Base de dados
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
BMC Genomics ; 15: 1154, 2014 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-25528190

RESUMO

BACKGROUND: The human neuroblastoma cell line, SH-SY5Y, is a commonly used cell line in studies related to neurotoxicity, oxidative stress, and neurodegenerative diseases. Although this cell line is often used as a cellular model for Parkinson's disease, the relevance of this cellular model in the context of Parkinson's disease (PD) and other neurodegenerative diseases has not yet been systematically evaluated. RESULTS: We have used a systems genomics approach to characterize the SH-SY5Y cell line using whole-genome sequencing to determine the genetic content of the cell line and used transcriptomics and proteomics data to determine molecular correlations. Further, we integrated genomic variants using a network analysis approach to evaluate the suitability of the SH-SY5Y cell line for perturbation experiments in the context of neurodegenerative diseases, including PD. CONCLUSIONS: The systems genomics approach showed consistency across different biological levels (DNA, RNA and protein concentrations). Most of the genes belonging to the major Parkinson's disease pathways and modules were intact in the SH-SY5Y genome. Specifically, each analysed gene related to PD has at least one intact copy in SH-SY5Y. The disease-specific network analysis approach ranked the genetic integrity of SH-SY5Y as higher for PD than for Alzheimer's disease but lower than for Huntington's disease and Amyotrophic Lateral Sclerosis for loss of function perturbation experiments.


Assuntos
Genômica , Neuroblastoma/patologia , Doença de Parkinson/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Elementos de DNA Transponíveis/genética , Perfilação da Expressão Gênica , Variação Genética , Humanos , Mutação INDEL , Proteômica
2.
Sci Transl Med ; 12(560)2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908004

RESUMO

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD.


Assuntos
Doença de Parkinson , Neurônios Dopaminérgicos , Éxons/genética , Humanos , Mutação/genética , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Splicing de RNA
3.
Gene Regul Syst Bio ; 10: 51-66, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27429547

RESUMO

Biological network models offer a framework for understanding disease by describing the relationships between the mechanisms involved in the regulation of biological processes. Crowdsourcing can efficiently gather feedback from a wide audience with varying expertise. In the Network Verification Challenge, scientists verified and enhanced a set of 46 biological networks relevant to lung and chronic obstructive pulmonary disease. The networks were built using Biological Expression Language and contain detailed information for each node and edge, including supporting evidence from the literature. Network scoring of public transcriptomics data inferred perturbation of a subset of mechanisms and networks that matched the measured outcomes. These results, based on a computable network approach, can be used to identify novel mechanisms activated in disease, quantitatively compare different treatments and time points, and allow for assessment of data with low signal. These networks are periodically verified by the crowd to maintain an up-to-date suite of networks for toxicology and drug discovery applications.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA