Transcriptome profiling in neurodegenerative disease

School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia.
Journal of Neuroscience Methods (Impact Factor: 2.05). 11/2010; 193(2):189-202. DOI: 10.1016/j.jneumeth.2010.08.018
Source: PubMed


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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    • "These data suggest the potential of NEP2 assays to serve as preclinical mRNA expression or enzyme activity markers for AD if expression levels in the brain mimic what is present in the blood or cerebrospinal fluid. Many neural pathologies including AD can be reflected in changes in gene expression, splicing, and protein profiles in blood and CSF, providing precedent for examining gene expression in these body fluids (Tang et al., 2005; Blennow et al., 2010; Courtney et al., 2010; Wu et al., 2011; Leuner et al., 2012; Mapstone et al., 2014). The search for new preclinical biomarkers is important given that the identification of biomarkers in AD has been relatively unsuccessful. "
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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 08/2014; 6:187. DOI:10.3389/fnagi.2014.00187 · 4.00 Impact Factor
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    • "PP1 dephosphorylates tau at five different sites in frontal lobe tissue. We show that PPP1CA levels are significantly reduced by 50% in frontal cortex of AD cases (Fig 5), which is consistent with previous transcriptome data of neurodegenerative diseases, including AD (Courtney et al, 2010). Importantly, knockdown of PPP1CA in primary hippocampal neurons strongly increased tau phosphorylation, most likely by activating Erk1/2 [Fig 4; "
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    ABSTRACT: Sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but no clear disease-initiating mechanism is known. Aβ deposits and neuronal tangles composed of hyperphosphorylated tau are characteristic for AD. Here, we analyze the contribution of microRNA-125b (miR-125b), which is elevated in AD. In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti-apoptotic factor Bcl-W are downregulated as direct targets of miR-125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl-W prevents miR-125b-induced tau phosphorylation, suggesting that they mediate the effects of miR-125b on tau. Conversely, suppression of miR-125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR-125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl-W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains. These data implicate miR-125b in the pathogenesis of AD by promoting pathological tau phosphorylation.
    The EMBO Journal 07/2014; 33(15). DOI:10.15252/embj.201387576 · 10.43 Impact Factor
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    • "Furthermore, problems with saturation and background signal do not exist as each molecule is individually sequenced and mapped to unique regions of the genome. RNA-Seq offers a larger dynamic range than microarray technology as no upper or lower levels exist in this quantification technique (Courtney et al., 2010). "
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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 04/2014; 6:75. DOI:10.3389/fnagi.2014.00075 · 4.00 Impact Factor
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