ABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia among the aging population. Although the incidence of the disease continues to increase, no cure has been developed. Effective treatment is restricted not only due to the lack of curative medicine, but also due to limited understanding of the underlying mechanisms and the difficulties in accurately diagnosing AD in its earliest stages prior to clinical symptoms. Micro (mi) RNAs (miR) have gained increasing attention in the investigation of neurodegenerative diseases. Previous reports have demonstrated that deregulation of miR146a5p is associated with the pathogenesis of human AD. In the present study, the coding region of primary (pri)miR146a in patients with AD was scanned and the rare C allele of rs2910164 was found to be associated with AD. Using reverse transcription quantitative polymerase chain reaction, it was demonstrated that site variation reduced the expression of mature miR146a5p. Notably, a reduction in the expression of miR146a5p led to less efficient inhibition of target genes, including Tolllike receptor (TLR)2, which is important in the pathogenesis of AD. Biological function investigations in RAW264.7 cells indicated that, compared with the G allele, the rare C allele upregulated the expression of tumor necrosis factorα following stimulation with ßamyloid. These findings suggested that one common polymorphism in primiR146a may contribute to the genetic predisposition to AD by disrupting the production of miR146a5p and affecting the expression and function of TLR2.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/pathology , MicroRNAs/genetics , MicroRNAs/metabolism , Polymorphism, Single Nucleotide/genetics , 3' Untranslated Regions , Aged , Aged, 80 and over , Alleles , Alzheimer Disease/metabolism , Animals , Base Sequence , Case-Control Studies , Cell Line , Female , Genes, Reporter , Genetic Predisposition to Disease , Genotype , HEK293 Cells , Humans , Male , Mice , MicroRNAs/chemistry , Middle Aged , Sequence Alignment , Toll-Like Receptor 2/chemistry , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/metabolism , Tumor Necrosis Factor-alpha/analysisABSTRACT
Parkinson disease (PD) is a common neurodegenerative disease. Most people with PD are idiopathic, with no specific known cause. Recently, several studies have indicated small proportion of PD cases may result from a mutation in some specific genes. However, the involved pathways of these genes and the co-expression patterns of associated pathways still remain unclear. Here, we aimed to systematically investigate PD related pathways by using microarray dataset GSE7621 from the public database library of gene expression omnibus and gene set enrichment analysis on the datasets. Furthermore, candidate transcription factors were also explored by distant regulatory elements software. As a result, 11 up-regulated pathways (such as glycosaminoglycan degradation) and 24 down-regulated pathways (such as ErbB signaling pathway and Long-term depression) were identified as PD related. Most of them were classified into the maps of human diseases, organismal system, and metabolism with no previous reports. Finally, we constructed co-expression networks of related pathways with the significant core genes and transcription factors, such as OCT and HNF3. All of these may be helpful to better understand the molecular mechanisms of human PD in genome wide.