Wang L, Xia J, Li J, Hagemann TL, Jones JR, Fraenkel E, Weitz DA, Zhang SC, Messing A, Feany MB. Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease. Nat Commun. 2018 May 15;9(1):1899. doi:10.1038/s41467-018-04269-7. PubMed PMID: 29765022; PubMed Central PMCID: PMC5954157.
From the abstract: "... Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. ... Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis."
Showing posts with label Alexander disease. Show all posts
Showing posts with label Alexander disease. Show all posts
Wednesday, January 30, 2019
Tuesday, December 27, 2016
Fly model of Alexander disease used in screen of FDA-approved drugs
Wang L, Hagemann TL, Messing A, Feany MB. An In Vivo Pharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease. J Neurosci. 2016 Feb 3;36(5):1445-55. PMID: 26843629; PubMed PMC4737762.
From the abstract: "... Here we use a simple genetic model of Alexander disease, a progressive and severe human degenerative nervous system disease ... to perform an in vivo screen of 1987 compounds, including many FDA-approved drugs and natural products. We identify four compounds capable of dose-dependent inhibition of nervous system toxicity. Focusing on one of these hits, glycopyrrolate, we confirm the role for muscarinic cholinergic signaling in pathogenesis using additional pharmacologic reagents and genetic approaches. ... We have therefore identified glial muscarinic signaling as a potential therapeutic target in Alexander disease, and possibly in other gliopathic disorders as well.
From the significance statement: "Despite the urgent need for better treatments for neurological diseases, drug development for these devastating disorders has been challenging. The effectiveness of traditional large-scale in vitro screens may be limited by the lack of the appropriate molecular, cellular, and structural environment. Using a simple Drosophila model of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds... Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles."
From the abstract: "... Here we use a simple genetic model of Alexander disease, a progressive and severe human degenerative nervous system disease ... to perform an in vivo screen of 1987 compounds, including many FDA-approved drugs and natural products. We identify four compounds capable of dose-dependent inhibition of nervous system toxicity. Focusing on one of these hits, glycopyrrolate, we confirm the role for muscarinic cholinergic signaling in pathogenesis using additional pharmacologic reagents and genetic approaches. ... We have therefore identified glial muscarinic signaling as a potential therapeutic target in Alexander disease, and possibly in other gliopathic disorders as well.
From the significance statement: "Despite the urgent need for better treatments for neurological diseases, drug development for these devastating disorders has been challenging. The effectiveness of traditional large-scale in vitro screens may be limited by the lack of the appropriate molecular, cellular, and structural environment. Using a simple Drosophila model of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds... Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles."
Saturday, February 27, 2016
Drosophila model of Alexander disease used to identify cholinergic signaling as potential therapeutic target
Wang L, Hagemann TL, Messing A, Feany MB. An In Vivo Pharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease. J Neurosci. 2016 Feb 3;36(5):1445-55. PMID: 26843629; PMCID: PMC4737762.
From the abstract: "... Using a simple Drosophila model of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds, and found that reducing muscarinic cholinergic signaling ameliorated clinical symptoms and oxidative stress in Alexander disease model flies and mice. Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles."
Wondering what is Alexander disease? Read about this rare nervous system disease at NIH Genetics Home Reference.
From the abstract: "... Using a simple Drosophila model of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds, and found that reducing muscarinic cholinergic signaling ameliorated clinical symptoms and oxidative stress in Alexander disease model flies and mice. Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles."
Wondering what is Alexander disease? Read about this rare nervous system disease at NIH Genetics Home Reference.
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