Abstract
Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non-demented controls, we investigated global disruptions in the co-regulation of genes in two neurodegenerative diseases, late-onset Alzheimer's disease (AD) and Huntington's disease (HD). We identified networks of differentially co-expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242-gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter-connected processes, chromatin organization and neural differentiation, and included DNA methyltransferases, DNMT1 and DNMT3A, of which we predicted the former but not latter as a key regulator. To validate the inter-connection of these two processes and our key regulator prediction, we generated two brain-specific knockout (KO) mice and show that Dnmt1 KO signature significantly overlaps with the subnetwork (P = 3.1 × 10−12), while Dnmt3a KO signature does not (P = 0.017).
Highlights
Different neurodegenerative diseases share similar dysfunctional phenotypes, such as misfolded protein aggregates, neuronal cell death, inflammation, and cognitive decline
We focused on systematic changes at the molecular level in the dorsolateral prefrontal cortex (DLPFC) from Alzheimer’s disease (AD) patients, Huntington’s disease (HD) patients, and non-demented subjects, since this brain region is commonly affected in both AD and HD (Armstrong, 2009; Roze et al, 2010)
We show for the first time that the global pattern of gene–gene coregulation in the human brain cortex is drastically altered in a shared fashion in neurodegenerative diseases like AD and HD, by employing a systematic differential co-expression (DC) analysis that complements conventional differential expression analysis for finding disease-associated changes
Summary
Different neurodegenerative diseases share similar dysfunctional phenotypes, such as misfolded protein aggregates, neuronal cell death, inflammation, and cognitive decline. The complexity of these diseases has hindered efforts to obtain a comprehensive view of common molecular mechanisms underlying their initiation or propagation, and thereby hampered development of drugs that could broadly halt neuronal loss in humans (Avila, 2010; Haass, 2010). This study focuses on two such complex diseases in humans, Alzheimer’s and Huntington’s, for which there is currently no effective intervention to halt or reverse the associated progressive cognitive decline. Late-onset Alzheimer’s disease (AD) is the most common form of dementia, accounting for up to 70% of all cases, and is characterized by an initial impact on memory with a subsequent progressive decline in cognitive functioning. Compared to AD, Huntington’s disease (HD) is a rare (~ 5/100,000) neurodegenerative disorder exhibiting cognitive dysfunction and severe motor
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