期刊
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
卷 41, 期 2, 页码 201-226出版社
WILEY
DOI: 10.1111/nan.12147
关键词
amyotrophic lateral sclerosis; cell models; fibroblasts; hypoxia response; microarray; microRNA; primary lateral sclerosis
资金
- Spastic Paraplegia Foundation
- Medical Research Council Dorothy Hodgkin Postgraduate Award
- Motor Neuron Disease Association [Goodall/Oct10/6066]
- Motor Neuron Disease Association/Medical Research Council Lady Edith Wolfson Fellowship [G0800380]
- European Union [HEALTH-F2-2008-223388]
- European Community [259867]
- EU Joint Programme - Neurodegenerative Disease Research (JPND), Sampling and biomarker OPtimization and Harmonization In ALS and other motor neuron diseases (SOPHIA)
- JPND - France, Agence Nationale de la Recherche (ANR)
- Germany, Bundesministerium fur Bildung und Forschung (BMBF)
- Ireland, Health Research Board (HRB)
- Italy, Ministero della Salute
- The Netherlands, The Netherlands Organisation for Health Research and Development (ZonMw)
- Poland, Narodowe Centrum Badan i Rozwoju
- Portugal, Fundacao a Ciencia e a Tecnologia
- Spain, Ministerio de Ciencia e Innovacion
- Switzerland, Schweizerischer Nationalfonds zur Forderung der wissenschaftlichen Forschung (SNF)
- Turkey, Tubitak
- United Kingdom, Medical Research Council (MRC)
- NIHR
- MRC [G0800380, MR/K000039/1] Funding Source: UKRI
- Medical Research Council [G0800380, MR/K000039/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10082] Funding Source: researchfish
AimsAmyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are two syndromic variants within the motor neurone disease spectrum. As PLS and most ALS cases are sporadic (SALS), this limits the availability of cellular models for investigating pathogenic mechanisms and therapeutic targets. The aim of this study was to use gene expression profiling to evaluate fibroblasts as cellular models for SALS and PLS, to establish whether dysregulated biological processes recapitulate those seen in the central nervous system and to elucidate pathways that distinguish the clinically defined variants of SALS and PLS. MethodsMicroarray analysis was performed on fibroblast RNA and differentially expressed genes identified. Genes in enriched biological pathways were validated by quantitative PCR and functional assays performed to establish the effect of altered RNA levels on the cellular processes. ResultsGene expression profiling demonstrated that whilst there were many differentially expressed genes in common between SALS and PLS fibroblasts, there were many more expressed specifically in the SALS fibroblasts, including those involved in RNA processing and the stress response. Functional analysis of the fibroblasts confirmed a significant decrease in miRNA production and a reduced response to hypoxia in SALS fibroblasts. Furthermore, metabolic gene changes seen in SALS, many of which were also evident in PLS fibroblasts, resulted in dysfunctional cellular respiration. ConclusionsThe data demonstrate that fibroblasts can act as cellular models for ALS and PLS, by establishing the transcriptional changes in known pathogenic pathways that confer subsequent functional effects and potentially highlight targets for therapeutic intervention.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据