Transcriptome profiling in neurodegenerative disease.
ABSTRACT Changes in gene expression and splicing patterns (that occur prior to the onset and during the progression of complex diseases) have become a major focus of neurodegenerative disease research. These signature patterns of gene expression provide clues about the mechanisms involved in the molecular pathogenesis of neurodegenerative disease and may facilitate the discovery of novel therapeutic drugs. With the development of array technologies and the very recent RNA-seq technique, our understanding of the pathogenesis of neurodegenerative disease is expanding exponentially. Here, we review the technologies involved in gene expression and splicing analysis and the related literature on three common neurodegenerative diseases: Alzheimer's disease, Parkinson's disease and Huntington's disease.
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ABSTRACT: Accumulation of the amyloid-beta (Aβ) peptide is a central factor in Alzheimer's disease (AD) pathogenesis as supported by continuing evidence. This review concisely summarizes this evidence supporting a critical role for Aβ in AD before discussing the clearance of this peptide. Mechanisms of clearance of Aβ are critical for preventing pathological elevations in Aβ concentration. Direct degradation of Aβ by endopeptidases has emerged as one important pathway for clearance. Of particular interest are endopeptidases that are sensitive to the neprilysin (NEP) inhibitors thiorphan and phosphoramidon (i.e., are "NEP-like") as these inhibitors induce a dramatic increase in Aβ levels in rodents. This review will focus on neprilysin-2 (NEP2), a NEP-like endopeptidase which cooperates with NEP to control Aβ levels in the brain. The evidence for the involvement of NEP2 in AD is discussed as well as the therapeutic relevance with regards to gene therapy and the development of molecular markers for the disease.Frontiers in Aging Neuroscience 01/2014; 6:187. · 5.20 Impact Factor
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ABSTRACT: One of the central research questions on the etiology of Alzheimer's disease (AD) is the elucidation of the molecular signatures triggered by the amyloid cascade of pathological events. Next-generation sequencing allows the identification of genes involved in disease processes in an unbiased manner. We have combined this technique with the analysis of two AD mouse models: (1) The 5XFAD model develops early plaque formation, intraneuronal Aβ aggregation, neuron loss, and behavioral deficits. (2) The Tg4-42 model expresses N-truncated Aβ4-42 and develops neuron loss and behavioral deficits albeit without plaque formation. Our results show that learning and memory deficits in the Morris water maze and fear conditioning tasks in Tg4-42 mice at 12 months of age are similar to the deficits in 5XFAD animals. This suggested that comparative gene expression analysis between the models would allow the dissection of plaque-related and -unrelated disease relevant factors. Using deep sequencing differentially expressed genes (DEGs) were identified and subsequently verified by quantitative PCR. Nineteen DEGs were identified in pre-symptomatic young 5XFAD mice, and none in young Tg4-42 mice. In the aged cohort, 131 DEGs were found in 5XFAD and 56 DEGs in Tg4-42 mice. Many of the DEGs specific to the 5XFAD model belong to neuroinflammatory processes typically associated with plaques. Interestingly, 36 DEGs were identified in both mouse models indicating common disease pathways associated with behavioral deficits and neuron loss.Frontiers in Aging Neuroscience 01/2014; 6:75. · 5.20 Impact Factor
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ABSTRACT: Whole genome expression microarrays can be used to study gene expression in blood, which comes in part from leukocytes, immature platelets, and red blood cells. Since these cells are important in the pathogenesis of stroke, RNA provides an index of these cellular responses to stroke. Our studies in rats have shown specific gene expression changes 24 hours after ischemic stroke, hemorrhage, status epilepticus, hypoxia, hypoglycemia, global ischemia, and following brief focal ischemia that simulated transient ischemic attacks in humans. Human studies show gene expression changes following ischemic stroke. These gene profiles predict a second cohort with >90% sensitivity and specificity. Gene profiles for ischemic stroke caused by large-vessel atherosclerosis and cardioembolism have been described that predict a second cohort with >85% sensitivity and specificity. Atherosclerotic genes were associated with clotting, platelets, and monocytes, and cardioembolic genes were associated with inflammation, infection, and neutrophils. These gene profiles predicted the cause of stroke in 58% of cryptogenic patients. These studies will provide diagnostic, prognostic, and therapeutic markers, and will advance our understanding of stroke in humans. New techniques to measure all coding and noncoding RNAs along with alternatively spliced transcripts will markedly advance molecular studies of human stroke.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 07/2011; 31(7):1513-31. · 5.46 Impact Factor