title: Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3.
abstract: 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 aDrosophilamodel 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 ofDrosophilacystathionine 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.
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Snijder
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Madina
authors.initials: M
authors.lastname: Baratashvili
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Grzeschik
authors.affiliation: Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Henri G D
authors.initials: HGD
authors.lastname: Leuvenink
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Lucas
authors.initials: L
authors.lastname: Kuijpers
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Sippie
authors.initials: S
authors.lastname: Huitema
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Onno
authors.initials: O
authors.lastname: Schaap
authors.affiliation: UMCG Microscopy and Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Ben N G
authors.initials: BNG
authors.lastname: Giepmans
authors.affiliation: UMCG Microscopy and Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Kuipers
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Jan Lj
authors.initials: JL
authors.lastname: Miljkovic
authors.affiliation: Faculty of Chemistry, University of Belgrade, Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mitrovic
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Eelke M
authors.initials: EM
authors.lastname: Bos
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Pascale F
authors.initials: PF
authors.lastname: Dijkers
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Eelke M
authors.initials: EM
authors.lastname: Bos
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Pascale F
authors.initials: PF
authors.lastname: Dijkers
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Wilfred F A den
authors.initials: WFAD
authors.lastname: Dunnen
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Milos R
authors.initials: MR
authors.lastname: Filipovic
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Harry van
authors.initials: HV
authors.lastname: Goor
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Ody C M
authors.initials: OCM
authors.lastname: Sibon