A novel systems analysis a synaptic gene network

摘要

ABSTRACT Alzheimer's disease (AD) is one of the most common diseases that afflict the elder population. The disease causes loss of memory, confusion and affects decision-making. The effort made in past decades led to the identification of some significant genes associated to AD. For example, 5% of the AD cases are associated to the APP gene, 20-50% are associated to ApoE4 and the remaining receive designations like ApoE4 non-carriers and sporadic AD. However, ApoE4 is considered to be a risk factor. Thus, most cases of AD still have an unclear etiology. This scenario began to change with the discovery that βA regulates the activity of the nAChRα7 nicotinic receptor by potentiating the receptor activity at low concentrations and inhibiting it at high concentrations. Together these and other observations make a strong case that AD might be a disease with an origination in synaptic dysfunction. However, that possibility poses a problem because synapses possess extremely complex networks and we still have a limited understanding of their complex regulation. Also, these networks are different in different neurons and not all of them are dedicated to cognitive function, which makes it extremely difficult to select the correct network and understand its organization and function. To overcome these hurdles, here we propose a systems approach to identify within a conserved synaptic network required for cognitive functions, those components effectively required for cognitive functions. Our preliminary data provide strong evidence that several genes we identified as part of a cholinergic synaptic network required in decision-making are associated either APP or βA. To understand how the mis-regulation of these genes leads to synaptic dysfunction we propose a series of experiments using Bubble Maps, a powerful platform developed by our group. This platform allows for analyzing complex 3D data with single cell resolution and geospatial referencing across multiple dimensions such as time, spatial location, levels of gene and protein expression, cell volumes, chromatin condensation, among others. Bubble Maps provides the first implementation of Geographical Information Systems (GIS) to retrieve fine resolution information of a complex cellular/molecular network. GIS is a robust system used for data management, map pattern analyses, spatial statistics, spatial location using attribute-based queries, and modeling spatial relationships. We expect that Aim1 will lead to the discover novel components of this synaptic network effectively required for decision-making, expand the number of second and third order interactors, and provide a broader view of the network and its edges; Aim 2 will validate the biological functions of these genes, establish regulatory relationships between them and define how these relationships contribute to proper connectivity and performance of these neurons; Aim 3 will test if disturbances in this network leads to synaptic dysfunction and neuronal death within entire brains. This research plan is geared toward the discovery of genes involved in synaptic dysfunction and is expected to increase our understanding of causative factors of AD and related neurodegenerative disease. RELEVANCE FOR HUMAN HEALTH In a growing elder population, neurodegenerative diseases such as Alzheimer's Disease, are increasingly becoming a public health concern. The use of systems approach to identify complex molecular networks associated to neurodegenerative disorders holds the potential to uncover key molecular players and develop targeted therapies to prevent or improve the condition of AD and related diseases.