PT  - JOURNAL ARTICLE
AU  - Sourena Soheili-Nezhad
AU  - Mojtaba Zarei
TI  - Mutational burden of giant synaptic genes may be the cause of Alzheimer’s disease
AID  - 10.1101/189712
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 189712
4099  - http://biorxiv.org/content/early/2017/09/15/189712.short
4100  - http://biorxiv.org/content/early/2017/09/15/189712.full
AB  - All of the drug trials of the Alzheimer’s disease (AD) have failed to slow progression of dementia in phase III studies, and the most effective therapeutic approach still remains controversial due to our incomplete understanding of AD pathophysiology. Amyloid beta (Aβ) and its cascade have been the primary focus of drug design efforts for more than a decade. However, mounting evidence indicates that mechanisms of AD etiopathogenesis are probably more complex than the previous reductionist models.Several genome-wide association studies (GWAS) have recently shed light on dark aspects of AD from a hypothesis-free point of view. While the newly-identified AD risk genes rather raise more questions than they answer in deciphering the amyloid cascade, as a potentially overlooked finding, many of them code for receptors and transducers of cell adhesion signaling cascades. Remarkably, the hallmark genetic factors of AD, including the amyloid precursor protein (APP), presenilins (PSEN) and APOE also take part in highly similar pathways of cell adhesion regulation and coordinate contact-guidance of neuronal growth cones in brain development, albeit these Aβ-independent roles remain highly underexplored.Here, we have revisited function of 27 AD risk genes in pathways of normal cell physiology. Our review clearly shows that a disrupted cell adhesion signaling nexus, rather than a protein aggregation process, is the central point of convergence in the unbiased genetic risk factors of AD. To further elucidate a potential relationship between aging and pathways of cell adhesion, we have conducted an exploratory bioinformatics analysis which revealed that cell adhesion is the most representative ontology of human genes larger than 500kb (p=8.0×10‒13), and these extremely large genes are mostly expressed in brain (p=2.1×10‒17) and selectively take part in synaptic composition (p=2.4×10‒14). As possible driving forces of brain evolution, large genes may coordinate complex wiring of synaptic circuits in neurodevelopment, and we suggest that they may also be vulnerable to the impact of somatic mutations in aging due to their exceptional sizes which will be assessed by statistical models. An exemplar of this notion is the giant APOE receptor Lrplb which is one of the most frequently deleted genes in various cancers and also represents the only brain-specific lipoprotein receptor. Our model, the large gene instability hypothesis, highlights alternate strategies for AD prevention, biomarker discovery and therapeutic design based on targeting genomic instability and synaptic adhesion.Abbreviations Alzheimer’s disease (AD), Amyloid precursor protein (APP), Genome-wide association study (GWAS), Focal adhesion kinase (FAK), Postsynaptic density (PSD), Presenilin (PSEN), Src family kinase (SFK)