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Systems-Level G Protein-Coupled Receptor Therapy Across a Neurodegenerative Continuum by the GLP-1 Receptor System.

Janssens J, Etienne H, Idriss S, Azmi A, Martin B, Maudsley S - Front Endocrinol (Lausanne) (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp , Antwerp , Belgium.

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.

No MeSH data available.


Related in: MedlinePlus

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 connected tissue–tissue signaling systems. Therapeutics that can interdict these perturbations at multiple sites in the disease process, i.e., “super-axis” therapeutics (dark blue) possess a much greater capacity to redress the systemic imbalances induced by disease than traditional non-axis therapeutics (light blue) that possess a limited functional repertoire.
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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 connected tissue–tissue signaling systems. Therapeutics that can interdict these perturbations at multiple sites in the disease process, i.e., “super-axis” therapeutics (dark blue) possess a much greater capacity to redress the systemic imbalances induced by disease than traditional non-axis therapeutics (light blue) that possess a limited functional repertoire.

Mentions: From multiple sources of information, both physiological and molecular biological, it now seems apparent that for many of the major CNS neurodegenerative disorders. i.e., AD, PD, and HD, their true pathophysiological spectrum is more widespread across the body than previously considered. In addition, it is clear that there are strong similarities between these neurodegenerative conditions, suggesting perhaps that a considerable proportion of these diseases is controlled by endogenous signaling systems that are merely perturbed by the initial disease locus, but then once activated stimulate a coherent series of pathophysiological activities. This potential system-wide disease–response axis clearly needs mechanisms to maintain its activity and also coordinate its functionality across diverse tissues in varied locations across the body. As we have previously discussed in the Section “Introduction,” the evolution of receptor signaling systems has had to deal with the challenges of intense somatic development from nematode worms to the hyper-complex Homo sapiens. The presence of the same receptor signaling system, in multiple specialized conformations, and in diverse tissues has been demonstrated for cholinergic ligands such as acetylcholine and peptidergic ligands such as gonadotropin-releasing hormone (GnRH: 12). With respect to a receptor signaling that may be preferentially involved in regulating the generic neurodegenerative “super-axis” system, we have identified a potential ligand–receptor system, the glucagon-like peptide 1 (GLP-1) system that may be critical for regulating pathophysiology, and therefore, also facilitating potential neurodegenerative remediation. Historically, GLP-1 has been considered primarily a gut incretin that is vitally involved, in concert with insulin, with glucose metabolism. GLP-1 is produced both in pancreatic α-cells as well as intestinal L-cells (154). Upon release into the circulation after food ingestion, GLP-1 facilitates glucose uptake by directly acting on pancreatic islet β-cells to enhance post-prandial insulin secretion (155). This process is mediated by GLP-1-mediated activation of a class B1 (secretin-like family) seven transmembrane spanning GPCRs (156, 157). The GLP-1 receptor (GLP-1R) has been shown to functionally interact with both heterotrimeric G proteins [Gαs, Gαq (158) as well as β-arrestin (159)]. This promiscuity of the GLP-1R therefore facilitates the ability to flexibly stimulate this receptor system to engender multiple downstream signaling cascades (1). Underpinning our assertion that the GLP-1 signaling system may represent an organism-wide functional “super-axis,” it has been demonstrated that components of the GLP-1 system are found in multiple tissues all the way across the body from the tongue, olfactory epithelia, CNS, heart, pancreas, intestine to reproductive tissues [Figure 1 (160–166)]. Considering the vital role of GLP-1 in energy metabolism and in maintaining the viability of multiple tissues, it is unsurprising that this receptor system has been transposed across the body. This super-axis therefore creates that possibility of multi-site, multi-tissue drug remediation of neurodegenerative disorders. Given the recent emergence of appreciation of the importance of metabolic support to diseases such as AD, PD, and HD (107, 114, 122), it is evident that advanced therapeutic control of the GLP-1 super-axis could therefore generate an excellent capacity to generate whole-organism systemic therapeutic actions. With respect to the connection between neuropathophysiology, it has been demonstrated that GLP-1 signaling is critically involved in metabolic regulation (165), controlling inflammatory processes (167), regulate gut–brain axis activity (168), control multiple sensory modalities (169, 170), modulate cardiovascular activity (171), coordinate sleep–wake cycles and circadian rhythms (172, 173). The GLP-1 system is likely to be only one of the several ligand–receptor systems that exerts a super-axis level of impact upon neurodegenerative mechanisms from multiple divergent initiator loci, however, due to considerable advances in therapeutic ligand design, it does represent an important target for the creation of a systems-level remedial agent. Concordant with the findings that the GLP-1 receptor system is intimately involved in multiple aspects of the neurodegenerative axes of AD, PD, and HD, it is unsurprising that ligands that can target this receptor system have been demonstrated to exert multiple remedial and effective actions (168, 174–178). The therapeutic regulation of such systems-level receptor systems clearly represents an excellent target for more nuanced therapeutic design as the efficacy of such “super-axis” compounds may be reinforced very strongly via multiple forms of tissue-to-tissue communication. Thus, it is likely that systems-level therapies may be far more efficacious than compared to receptor-modulating ligands that are only targeted to one specific component of the neurodegenerative axis (Figure 2). In this context of the potential “super-axis” therapies, a more advanced appreciation of the functional pharmacology of these receptor–ligand systems is vital. The generation of novel tissue and/or signal-selective GLP-1 modulating agents (1, 10, 179) is therefore perhaps one of the most important future fields of study for neurodegeneration.


Systems-Level G Protein-Coupled Receptor Therapy Across a Neurodegenerative Continuum by the GLP-1 Receptor System.

Janssens J, Etienne H, Idriss S, Azmi A, Martin B, Maudsley S - Front Endocrinol (Lausanne) (2014)

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 connected tissue–tissue signaling systems. Therapeutics that can interdict these perturbations at multiple sites in the disease process, i.e., “super-axis” therapeutics (dark blue) possess a much greater capacity to redress the systemic imbalances induced by disease than traditional non-axis therapeutics (light blue) that possess a limited functional repertoire.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150252&req=5

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 connected tissue–tissue signaling systems. Therapeutics that can interdict these perturbations at multiple sites in the disease process, i.e., “super-axis” therapeutics (dark blue) possess a much greater capacity to redress the systemic imbalances induced by disease than traditional non-axis therapeutics (light blue) that possess a limited functional repertoire.
Mentions: From multiple sources of information, both physiological and molecular biological, it now seems apparent that for many of the major CNS neurodegenerative disorders. i.e., AD, PD, and HD, their true pathophysiological spectrum is more widespread across the body than previously considered. In addition, it is clear that there are strong similarities between these neurodegenerative conditions, suggesting perhaps that a considerable proportion of these diseases is controlled by endogenous signaling systems that are merely perturbed by the initial disease locus, but then once activated stimulate a coherent series of pathophysiological activities. This potential system-wide disease–response axis clearly needs mechanisms to maintain its activity and also coordinate its functionality across diverse tissues in varied locations across the body. As we have previously discussed in the Section “Introduction,” the evolution of receptor signaling systems has had to deal with the challenges of intense somatic development from nematode worms to the hyper-complex Homo sapiens. The presence of the same receptor signaling system, in multiple specialized conformations, and in diverse tissues has been demonstrated for cholinergic ligands such as acetylcholine and peptidergic ligands such as gonadotropin-releasing hormone (GnRH: 12). With respect to a receptor signaling that may be preferentially involved in regulating the generic neurodegenerative “super-axis” system, we have identified a potential ligand–receptor system, the glucagon-like peptide 1 (GLP-1) system that may be critical for regulating pathophysiology, and therefore, also facilitating potential neurodegenerative remediation. Historically, GLP-1 has been considered primarily a gut incretin that is vitally involved, in concert with insulin, with glucose metabolism. GLP-1 is produced both in pancreatic α-cells as well as intestinal L-cells (154). Upon release into the circulation after food ingestion, GLP-1 facilitates glucose uptake by directly acting on pancreatic islet β-cells to enhance post-prandial insulin secretion (155). This process is mediated by GLP-1-mediated activation of a class B1 (secretin-like family) seven transmembrane spanning GPCRs (156, 157). The GLP-1 receptor (GLP-1R) has been shown to functionally interact with both heterotrimeric G proteins [Gαs, Gαq (158) as well as β-arrestin (159)]. This promiscuity of the GLP-1R therefore facilitates the ability to flexibly stimulate this receptor system to engender multiple downstream signaling cascades (1). Underpinning our assertion that the GLP-1 signaling system may represent an organism-wide functional “super-axis,” it has been demonstrated that components of the GLP-1 system are found in multiple tissues all the way across the body from the tongue, olfactory epithelia, CNS, heart, pancreas, intestine to reproductive tissues [Figure 1 (160–166)]. Considering the vital role of GLP-1 in energy metabolism and in maintaining the viability of multiple tissues, it is unsurprising that this receptor system has been transposed across the body. This super-axis therefore creates that possibility of multi-site, multi-tissue drug remediation of neurodegenerative disorders. Given the recent emergence of appreciation of the importance of metabolic support to diseases such as AD, PD, and HD (107, 114, 122), it is evident that advanced therapeutic control of the GLP-1 super-axis could therefore generate an excellent capacity to generate whole-organism systemic therapeutic actions. With respect to the connection between neuropathophysiology, it has been demonstrated that GLP-1 signaling is critically involved in metabolic regulation (165), controlling inflammatory processes (167), regulate gut–brain axis activity (168), control multiple sensory modalities (169, 170), modulate cardiovascular activity (171), coordinate sleep–wake cycles and circadian rhythms (172, 173). The GLP-1 system is likely to be only one of the several ligand–receptor systems that exerts a super-axis level of impact upon neurodegenerative mechanisms from multiple divergent initiator loci, however, due to considerable advances in therapeutic ligand design, it does represent an important target for the creation of a systems-level remedial agent. Concordant with the findings that the GLP-1 receptor system is intimately involved in multiple aspects of the neurodegenerative axes of AD, PD, and HD, it is unsurprising that ligands that can target this receptor system have been demonstrated to exert multiple remedial and effective actions (168, 174–178). The therapeutic regulation of such systems-level receptor systems clearly represents an excellent target for more nuanced therapeutic design as the efficacy of such “super-axis” compounds may be reinforced very strongly via multiple forms of tissue-to-tissue communication. Thus, it is likely that systems-level therapies may be far more efficacious than compared to receptor-modulating ligands that are only targeted to one specific component of the neurodegenerative axis (Figure 2). In this context of the potential “super-axis” therapies, a more advanced appreciation of the functional pharmacology of these receptor–ligand systems is vital. The generation of novel tissue and/or signal-selective GLP-1 modulating agents (1, 10, 179) is therefore perhaps one of the most important future fields of study for neurodegeneration.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp , Antwerp , Belgium.

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.

No MeSH data available.


Related in: MedlinePlus