Molecular Medicine

, Volume 21, Issue 1, pp 758–768 | Cite as

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

  • Pauline M. Snijder
  • Madina Baratashvili
  • Nicola A. Grzeschik
  • Henri G. D. Leuvenink
  • Lucas Kuijpers
  • Sippie Huitema
  • Onno Schaap
  • Ben N. G. Giepmans
  • Jeroen Kuipers
  • Jan Lj Miljkovic
  • Aleksandra Mitrovic
  • Eelke M. Bos
  • Csaba Szabó
  • Harm H. Kampinga
  • Pascale F. Dijkers
  • Wilfred F. A. den Dunnen
  • Milos R. Filipovic
  • Harry van Goor
  • Ody C. M. Sibon
Research Article


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.



This work was supported by a VICI grant (to OCM Sibon) and a grant from the Jan Kornelis de Cock Foundation (to PM Snijder). Part of this work was performed at the UMCG Microscopy and Imaging Center (UMIC), sponsored by ZonMW grant 91111.006.

The authors express their gratitude to Martha Elwenspoek, Marian Bulthuis and Yi Xian Li for excellent technical support and to Bart Kanon and Jan Vonk for support and valuable advice.

Supplementary material

10020_2015_2101758_MOESM1_ESM.pdf (2.5 mb)
Supplementary material, approximately 2.48 MB.


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Authors and Affiliations

  • Pauline M. Snijder
    • 1
  • Madina Baratashvili
    • 2
  • Nicola A. Grzeschik
    • 2
  • Henri G. D. Leuvenink
    • 3
  • Lucas Kuijpers
    • 2
  • Sippie Huitema
    • 1
  • Onno Schaap
    • 2
  • Ben N. G. Giepmans
    • 4
  • Jeroen Kuipers
    • 4
  • Jan Lj Miljkovic
    • 5
  • Aleksandra Mitrovic
    • 6
  • Eelke M. Bos
    • 1
  • Csaba Szabó
    • 7
  • Harm H. Kampinga
    • 2
  • Pascale F. Dijkers
    • 2
  • Wilfred F. A. den Dunnen
    • 1
  • Milos R. Filipovic
    • 5
  • Harry van Goor
    • 1
  • Ody C. M. Sibon
    • 2
  1. 1.Department of Pathology and Medical Biology, University Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
  2. 2.Department of Cell Biology, University Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
  3. 3.Department of Surgery, University Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
  4. 4.UMCG Microscopy and Imaging Center, University Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
  5. 5.Department of Chemistry and PharmacyFriedrich-Alexander University of Erlangen-NurembergErlangenGermany
  6. 6.Faculty of ChemistryUniversity of BelgradeBelgradeSerbia
  7. 7.Department of AnesthesiologyUniversity of Texas Medical BranchGalvestonUSA

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