Yeh PA, Liu YH, Chu WC, Liu JY, Sun YH. Glial expression of disease-associated poly-glutamine proteins impairs the blood-brain barrier in Drosophila. Hum Mol Genet. 2018 Jul 15;27(14):2546-2562. PMID: 29726932.
From the abstract: "Expansion of poly-glutamine (polyQ) stretches in several proteins has been linked to neurodegenerative diseases. The effects of polyQ-expanded proteins on neurons have been extensively studied, but their effects on glia remain unclear. We found that expression of distinct polyQ proteins exclusively in all glia or specifically in the blood-brain barrier (BBB) and blood-retina barrier (BRB) glia caused cell-autonomous impairment of BBB/BRB integrity ... Furthermore, we also found that BBB/BRB leakage in Drosophila is reflected in reversed waveform polarity on the basis of electroretinography (ERG) ... The polyQ-expanded protein Atxn3-84Q forms aggregates, induces BBB/BRB leakage, restricts Drosophila lifespan and reduces the level of Repo ... Expression of Repo in BBB/BRB glia can rescue BBB/BRB leakage ... Coexpression of the chaperon HSP40 and HSP70 effectively rescues the effects of Atxn3-84Q ... coexpression of wild-type Atxn3-27Q can also rescue BBB/BRB impairment, suggesting that normal polyQ protein may have a protective function."
Showing posts with label PolyQ Disease. Show all posts
Showing posts with label PolyQ Disease. Show all posts
Saturday, April 20, 2019
Monday, July 9, 2018
Drosophila used in study related to polyQ-related neurodegeneration
Zhang Q, Chen ZS, An Y, Liu H, Hou Y, Li W, Lau KF, Koon AC, Ngo JCK, Chan HYE. A peptidylic inhibitor for neutralizing expanded CAG RNA-induced nucleolar stress in polyglutamine diseases. RNA. 2018 Apr;24(4):486-498. PMID: 29295891; PMCID: PMC5855950.
Abstract: "Polyglutamine (polyQ) diseases are a class of progressive neurodegenerative disorders characterized by the expression of both expanded CAG RNA and misfolded polyQ protein. We previously reported that the direct interaction between expanded CAG RNA and nucleolar protein nucleolin (NCL) impedes preribosomal RNA (pre-rRNA) transcription, and eventually triggers nucleolar stress-induced apoptosis in polyQ diseases. Here, we report that a 21-amino acid peptide, named "beta-structured inhibitor for neurodegenerative diseases" (BIND), effectively suppresses toxicity induced by expanded CAG RNA. When administered to a cell model, BIND potently inhibited cell death induced by expanded CAG RNA with an IC50 value of ∼0.7 µM. We showed that the function of BIND is dependent on Glu2, Lys13, Gly14, Ile18, Glu19, and Phe20. BIND treatment restored the subcellular localization of nucleolar marker protein and the expression level of pre-45s rRNA Through isothermal titration calorimetry analysis, we demonstrated that BIND suppresses nucleolar stress via a direct interaction with CAG RNA in a length-dependent manner. The mean binding constants (KD) of BIND to SCA2CAG22 , SCA2CAG42 , SCA2CAG55 , and SCA2CAG72 RNA are 17.28, 5.60, 4.83, and 0.66 µM, respectively. In vivo, BIND ameliorates retinal degeneration and climbing defects, and extends the lifespan of Drosophila expressing expanded CAG RNA. These effects suggested that BIND can suppress neurodegeneration in diverse polyQ disease models in vivo and in vitro without exerting observable cytotoxic effect. Our results collectively demonstrated that BIND is an effective inhibitor of expanded CAG RNA-induced toxicity in polyQ diseases."
Abstract: "Polyglutamine (polyQ) diseases are a class of progressive neurodegenerative disorders characterized by the expression of both expanded CAG RNA and misfolded polyQ protein. We previously reported that the direct interaction between expanded CAG RNA and nucleolar protein nucleolin (NCL) impedes preribosomal RNA (pre-rRNA) transcription, and eventually triggers nucleolar stress-induced apoptosis in polyQ diseases. Here, we report that a 21-amino acid peptide, named "beta-structured inhibitor for neurodegenerative diseases" (BIND), effectively suppresses toxicity induced by expanded CAG RNA. When administered to a cell model, BIND potently inhibited cell death induced by expanded CAG RNA with an IC50 value of ∼0.7 µM. We showed that the function of BIND is dependent on Glu2, Lys13, Gly14, Ile18, Glu19, and Phe20. BIND treatment restored the subcellular localization of nucleolar marker protein and the expression level of pre-45s rRNA Through isothermal titration calorimetry analysis, we demonstrated that BIND suppresses nucleolar stress via a direct interaction with CAG RNA in a length-dependent manner. The mean binding constants (KD) of BIND to SCA2CAG22 , SCA2CAG42 , SCA2CAG55 , and SCA2CAG72 RNA are 17.28, 5.60, 4.83, and 0.66 µM, respectively. In vivo, BIND ameliorates retinal degeneration and climbing defects, and extends the lifespan of Drosophila expressing expanded CAG RNA. These effects suggested that BIND can suppress neurodegeneration in diverse polyQ disease models in vivo and in vitro without exerting observable cytotoxic effect. Our results collectively demonstrated that BIND is an effective inhibitor of expanded CAG RNA-induced toxicity in polyQ diseases."
Friday, August 21, 2015
Review--Drosophila research contribution to understaning polyQ diseases
Xu Z, Tito A, Rui YN, Zhang S. Studying Polyglutamine Diseases in Drosophila. Exp Neurol. 2015 Aug 6. pii: S0014-4886(15)30063-7. PMID: 26257024.
From the abstract: "Polyglutamine (polyQ) diseases are a family of dominantly transmitted neurodegenerative disorders caused by an abnormal expansion of CAG trinucleotide repeats in the protein-coding regions of the respective disease-causing genes. ... Over the past two decades, Drosophila has proven to be successful in modeling this family of neurodegenerative disorders, including the faithful recapitulation of pathological features such as ... neuronal degeneration. Additionally, it has been valuable in probing the pathogenic mechanisms, in identifying and evaluating disease modifiers, and in helping elucidate the normal functions of disease-causing genes. Knowledge learned from this simple invertebrate organism has had a large impact on our understanding of these devastating brain diseases."
From the abstract: "Polyglutamine (polyQ) diseases are a family of dominantly transmitted neurodegenerative disorders caused by an abnormal expansion of CAG trinucleotide repeats in the protein-coding regions of the respective disease-causing genes. ... Over the past two decades, Drosophila has proven to be successful in modeling this family of neurodegenerative disorders, including the faithful recapitulation of pathological features such as ... neuronal degeneration. Additionally, it has been valuable in probing the pathogenic mechanisms, in identifying and evaluating disease modifiers, and in helping elucidate the normal functions of disease-causing genes. Knowledge learned from this simple invertebrate organism has had a large impact on our understanding of these devastating brain diseases."
Tuesday, October 22, 2013
Fly poly-Q disease model and heat-shock proteins. Recent report.
Kuo Y, Ren S, Lao U, Edgar BA, Wang T. Suppression of polyglutamine protein toxicity by co-expression of a heat-shock protein 40 and a heat-shock protein 110. Cell Death Dis. 2013 Oct 3;4:e833. PMID: 24091676.
Tuesday, November 20, 2012
Poly-Q large-scale screen. Recent report.
Voßfeldt H, Butzlaff M, Prüßing K, Ní Chárthaigh RA, Karsten P, Lankes A, Hamm S, Simons M, Adryan B, Schulz JB, Voigt A. Large-scale screen for modifiers of ataxin-3-derived polyglutamine-induced toxicity in Drosophila. PLoS One. 2012;7(11):e47452. doi: 10.1371/journal.pone.0047452. PubMed PMID: 23139745; PubMed Central PMCID: PMC3489908.
Saturday, November 17, 2012
Poly-Q neurodegeneration, p53, nucleoli and flies. Recent report.
This report describes use of Drosophila and mammalian systems to uncover links between PolyQ disease and nucleolar stress.
Tsoi H, Lau TC, Tsang SY, Lau KF, Chan HY. CAG expansion induces nucleolar stress in polyglutamine diseases. Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13428-33. doi: 10.1073/pnas.1204089109. PubMed PMID: 22847428; PubMed Central PMCID: PMC3421186.
Tsoi H, Lau TC, Tsang SY, Lau KF, Chan HY. CAG expansion induces nucleolar stress in polyglutamine diseases. Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13428-33. doi: 10.1073/pnas.1204089109. PubMed PMID: 22847428; PubMed Central PMCID: PMC3421186.
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