Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3.

Autor: Snijder PM; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Baratashvili M; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Grzeschik NA; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Leuvenink HGD; Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Kuijpers L; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Huitema S; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Schaap O; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Giepmans BNG; UMCG Microscopy and Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Kuipers J; UMCG Microscopy and Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Miljkovic JL; Department of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany., Mitrovic A; Faculty of Chemistry, University of Belgrade, Belgrade, Serbia., Bos EM; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Szabó C; Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America., Kampinga HH; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Dijkers PF; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Bos EM; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Szabó C; Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America., Kampinga HH; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Dijkers PF; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Dunnen WFAD; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Filipovic MR; Department of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany., Goor HV; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Sibon OCM; Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Jazyk: angličtina
Zdroj: Molecular medicine (Cambridge, Mass.) [Mol Med] 2016 Jan; Vol. 21 (1), pp. 758-768. Date of Electronic Publication: 2015 Oct 13.
DOI: 10.2119/molmed.2015.00221
Abstrakt: Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ataxin-3 ( ATXN3 ) gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative disease. There is no cure that halts or reverses the progressive neurodegeneration of SCA3. Here we show that overexpression of cystathionine γ-lyase, a central enzyme in cysteine metabolism, is protective in a Drosophila model for SCA3. SCA3 flies show eye degeneration, increased oxidative stress, insoluble protein aggregates, reduced levels of protein persulfidation and increased activation of the innate immune response. Overexpression of Drosophila cystathionine γ-lyase restores protein persulfidation, decreases oxidative stress, dampens the immune response and improves SCA3-associated tissue degeneration. Levels of insoluble protein aggregates are not altered; therefore, the data implicate a modifying role of cystathionine γ-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine γ-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine γ-lyase expression or activity are attractive candidates for future therapies.
Databáze: MEDLINE
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