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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    • "RNA-Seq has a higher resolution, lower levels of background noise, lower requirement of input RNA and can detect a greater range of expression levels[69]. The most important aspect of RNA-Seq is that it can be used to assemble transcriptomes de novo; this allows for the discovery of un-annotated transcripts and novel splicing events[69]. This ability makes RNA-Seq an ideal tool for the identification species-and tissue-specific lncRNAs, many of which have not been previously annotated. "
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    ABSTRACT: Over the past decade, the focus of molecular biology has shifted from being predominately DNA and protein-centric to having a greater appreciation of RNA. It is now accepted that the genome is pervasively transcribed in tissue- and cell-specific manner, to produce not only protein-coding RNAs, but also an array of noncoding RNAs (ncRNAs). Many of these ncRNAs have been found to interact with DNA, protein and other RNA molecules where they exert regulatory functions. Long ncRNAs (lncRNAs) are a subclass of ncRNAs that are particularly interesting due to their cell-specific and species-specific expression patterns and unique conservation patterns. Currently, individual lncRNAs have been classified functionally; however, for the vast majority the functional relevance is unknown. To better categorize lncRNAs, an understanding of their specific expression patterns and evolutionary constraints are needed.
    Preview · Article · Jan 2015
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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.
    Full-text · Article · Aug 2014 · Frontiers in Aging Neuroscience
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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.
    Full-text · Article · Jul 2014 · The EMBO Journal
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