Assembly and Interrogation of Alzheimer’s Disease Genetic Networks Reveal Novel Regulators of Progression

Abstract

Alzheimer’s disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression.

Neuroanatomical Distribution of DEK Protein in Corticolimbic Circuits Associated with Learning and Memory in Adult Male and Female Mice

“…To date, the only factors known to directly modulate DEK transcription are E2F-1, YY-1, NF-Y and estrogen receptor (ER)α (Carro et al 2006, Privette Vinnedge et al 2012, Sitwala et al 2002). Consistent with DEK overexpression in tumors or proliferating cells, these factors are also expressed at higher rates in cancer (Privette Vinnedge et al 2011) and are associated with either cellular or behavioral indices of learning and memory (Aubry et al 2015, Bean et al 2014, Gurtner et al 2010, Rossner et al 2006, Ting et al 2014, Vierk et al 2014). While DEK is known for its role in cancer and autoimmune diseases (Matrka et al 2015, Mor-Vaknin et al 2011, Pease et al 2015), its function in the CNS has not been described.…”

Exceptionally long 5′ UTR short tandem repeats specifically linked to primates

“…For example, the gene, ZMYM3, contains the longest STR in a human gene 5′ UTR. Remarkably, this gene has been listed as the top three master regulators of Alzheimer's disease progression (Aubry et al, 2015). In another remarkable example, the human gene, DAZAP1, contains the longest tri-nucleotide The numbers following slashes represent number of repeats.…”

The recurrent architecture of tumour initiation, progression and drug sensitivity

“…In addition, their use in non-cancer phenotypes has helped to elucidate an equivalent disease checkpoint architecture in neurological phenotypes — including amyotrophic lateral sclerosis (ALS) 53 , Alzheimer disease 7,54 , Parkinson disease 55 and alcohol addiction 56 — and in developmental phenotypes, from regulation of germinal centre formation 39 to stem cell pluripotency 57 . As briefly summarized below, these examples further outline the role of tumour checkpoint MRs in regulating disease dystasis and their unique nature compared with their physiological counterpart involved in homeostatic control.…”