Systems-level G protein-coupled receptor therapy across a neurodegenerative continuum by the GLP-1 receptor system

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Abstract

With our increasing appreciation of the true complexity of diseases and pathophysiologies, it is clear that this knowledge needs to inform the future development of pharmacotherapeutics. For many disorders, the disease mechanism itself is a complex process spanning multiple signaling networks, tissues, and organ systems. Identifying the precise nature and locations of the pathophysiology is crucial for the creation of systemically effective drugs. Diseases once considered constrained to a limited range of organ systems, e.g., central neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington' disease (HD), the role of multiple central and peripheral organ systems in the etiology of such diseases is now widely accepted. With this knowledge, it is increasingly clear that these seemingly distinct neurodegenerative disorders (AD, PD, and HD) possess multiple pathophysiological similarities thereby demonstrating an inter-related continuum of disease-related molecular alterations. With this systems-level appreciation of neurodegenerative diseases, it is now imperative to consider that pharmacotherapeutics should be developed specifically to address the systemic imbalances that create the disorders. Identification of potential systems-level signaling axes may facilitate the generation of therapeutic agents with synergistic remedial activity across multiple tissues, organ systems, and even diseases. Here, we discuss the potentially therapeutic systems-level interaction of the glucagon-like peptide 1 (GLP-1) ligand-receptor axis with multiple aspects of the AD, PD, and HD neurodegenerative continuum.

Figures

  • FIGURE 1 | Glucagon-like peptide 1 (GLP-1) ligand and receptor system super-axis are shown. The expression of the ligand and receptor components of the GLP-1 system spans the whole human body. The repetitive expression of this GPCR system in multiple tissue types reinforces the importance of maintaining energy balance across the whole organism
  • FIGURE 2 | Super-axis remediation of complex systemic disorders is shown. Classical neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease (AD, PD, and HD) represent intensely complex pathophysiological perturbations of normal systemic biology. These neurodegenerative disorders generate their full phenotypes through the disruption of multiple

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Janssens, J., Etienne, H., Idriss, S., Azmi, A., Martin, B., & Maudsley, S. (2014). Systems-level G protein-coupled receptor therapy across a neurodegenerative continuum by the GLP-1 receptor system. Frontiers in Endocrinology. Frontiers Media S.A. https://doi.org/10.3389/fendo.2014.00142

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