Unveiling Clusters of RNA Transcript Pairs Associated with Markers of Alzheimer’s Disease Progression

Abstract

BackgroundOne primary goal of transcriptomic studies is identifying gene expression patterns correlating with disease progression. This is usually achieved by considering transcripts that independently pass an arbitrary threshold (e.g. p<0.05). In diseases involving severe perturbations of multiple molecular systems, such as Alzheimer’s disease (AD), this univariate approach often results in a large list of seemingly unrelated transcripts. We utilised a powerful multivariate clustering approach to identify clusters of RNA biomarkers strongly associated with markers of AD progression. We discuss the value of considering pairs of transcripts which, in contrast to individual transcripts, helps avoid natural human transcriptome variation that can overshadow disease-related changes.Methodology/Principal FindingsWe re-analysed a dataset of hippocampal transcript levels in nine controls and 22 patients with varying degrees of AD. A large-scale clustering approach determined groups of transcript probe sets that correlate strongly with measures of AD progression, including both clinical and neuropathological measures and quantifiers of the characteristic transcriptome shift from control to severe AD. This enabled identification of restricted groups of highly correlated probe sets from an initial list of 1,372 previously published by our group. We repeated this analysis on an expanded dataset that included all pair-wise combinations of the 1,372 probe sets. As clustering of this massive dataset is unfeasible using standard computational tools, we adapted and re-implemented a clustering algorithm that uses external memory algorithmic approach. This identified various pairs that strongly correlated with markers of AD progression and highlighted important biological pathways potentially involved in AD pathogenesis.Conclusions/SignificanceOur analyses demonstrate that, although there exists a relatively large molecular signature of AD progression, only a small number of transcripts recurrently cluster with different markers of AD progression. Furthermore, considering the relationship between two transcripts can highlight important biological relationships that are missed when considering either transcript in isolation.

RanBP9 overexpression reduces dendritic arbor and spine density

“…Consistent with our report, RanBP9 was recently found to be within the clusters of RNA transcript pairs associated with markers of AD progression (Arefin et al, 2012), supporting our idea that RanBP9 might play a critical role in the pathogenesis of AD. Our subsequent investigations using transgenic mice overexpressing RanBP9 confirmed that RanBP9 in fact regulates Aβ generation and amyloid plaque burden in vivo in the mouse brain.…”

COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

“…The RanBP9-LisH Domain Binds COPS5 in the Yeast Twohybrid System-Recently, RanBP9 was found to be within the clusters of RNA transcript pairs associated with markers of AD progression, suggesting that RanBP9 might play a pathogenic role in AD (9). In fact, down-regulation of RanBP9 significantly reduced A␤ generation in primary neuronal cultures (11), implying that RanBP9 regulates A␤ generation.…”

“…Recently, RanBP9 was found to be within the clusters of RNA transcript pairs associated with markers of AD progression, suggesting that RanBP9 might contribute to the pathogenesis of AD (9). In fact, even before this finding, we showed for the first time that RanBP9 protein levels are increased 6-fold in AD brains (10) and that RanBP9 overexpression increases A␤ generation 4-fold in cell cultures by increasing ␤-secretase-mediated processing of APP (11) and also increases amyloid plaques in mouse brains (12), which, in turn, leads to a significant loss of synaptic proteins (12).…”

RanBP9 overexpression accelerates loss of dendritic spines in a mouse model of Alzheimer's disease

“…RanBP9 is a multidomain protein that functions as a scaffolding protein by assembling multiprotein complexes in different subcellular regions, thereby mediates diverse cellular functions (Murrin and Talbot, 2007; Suresh et al, 2012). Recently, RanBP9 was found to be within the clusters of RNA transcript pairs associated with markers of AD progression (Arefin et al, 2012), suggesting that RanBP9 might contribute to the pathogenesis of AD. In fact, even before this discovery, we showed for the first time that RanBP9 increased Aβ generation by 4-fold in a variety of cell cultures (Lakshmana et al, 2010), primary neurons (Lakshmana et al, 2009) as well as mouse brains (Lakshmana et al, 2012), consequently leading to increased amyloid plaque burden (Lakshmana et al, 2012).…”