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

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.

Nuclear GIT2 Is an ATM Substrate and Promotes DNA Repair

“…Disruption of GIT2 expression or functionality may lead to compromised DNA repair in the CNS, eventually leading to the premature induction of neuronal aging-related pathogenic mechanisms. Advanced neuronal aging and accumulated damage may underpin several well-characterized neurodegenerative disorders, such as Alzheimer's or Parkinson's disease (55). Therefore, further elucidation of the role(s) of GIT2, including the potential contribution of naturally occurring GIT2 SQ-TQ motif mutations, in maintaining DNA integrity in these processes would be of interest.…”

Hippocampal Transcriptomic and Proteomic Alterations in the BTBR Mouse Model of Autism Spectrum Disorder

“…The Wfs1 protein has long been implicated in the generation of its titular disease, Wolfram Syndrome, which is an inherited autosomal recessive neurodegenerative disorder (Inoue et al, 1998 ; Hardy et al, 1999 ; for review see Rigoli et al, 2011 ) associated with visual/auditory sensory atrophy and also significant diabetic pathophysiologies. Since many neurodegenerative phenotypes are strongly influenced by metabolic activity (Cai et al, 2012 ; Janssens et al, 2014 ; Wang et al, 2014 ), we investigated whether the consistent alteration of Wfs1 in BTBR mice was associated with any systemic metabolic alterations.…”

GLP‑1R agonists ameliorate peripheral nerve dysfunction and inflammation via p38 MAPK/NF‑κB signaling pathways in streptozotocin‑induced diabetic rats

“…GLP-1R agonists are approved to improve glycemic control in diabetes patients, based on their abilities to slow gastric emptying, to suppress glucagon secretion and to stimulate insulin secretion from pancreatic β-cells in a glucose-dependent manner (29). In addition to their insulinotropic actions, certain studies have demonstrated that GLP-1R agonists exhibit neurotrophic and neuroprotective properties in certain neurons and neural cells (16,(30)(31)(32)(33)(34). GLP-1 receptors are present on sciatic nerve axons, Schwann cells and dorsal root ganglia (DRG) sensory neurons of normal and diabetic rats (11).…”