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 Szabo, Harm H. Kampinga, Pascale F. Dijkers, Wilfred F A Den Dunnen, Milos R. Filipovic, Harry Van Goor, Ody C M Sibon

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)758-768
Number of pages11
JournalMolecular Medicine
Volume21
DOIs
StatePublished - Aug 24 2015

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Machado-Joseph Disease
Cystathionine
Lyases
Oxidative Stress
Drosophila
Proteins
Poisons
Heat-Shock Proteins
Innate Immunity
Diptera
Neurodegenerative Diseases
Cysteine
Inflammation
Brain
Enzymes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Snijder, P. M., Baratashvili, M., Grzeschik, N. A., Leuvenink, H. G. D., Kuijpers, L., Huitema, S., ... Sibon, O. C. M. (2015). Overexpression of cystathionine γ-Lyase suppresses detrimental effects of spinocerebellar ataxia type 3. Molecular Medicine, 21, 758-768. https://doi.org/10.2119/molmed.2015.00221

Overexpression of cystathionine γ-Lyase suppresses detrimental effects of spinocerebellar ataxia type 3. / Snijder, Pauline M.; Baratashvili, Madina; Grzeschik, Nicola A.; Leuvenink, Henri G D; Kuijpers, Lucas; Huitema, Sippie; Schaap, Onno; Giepmans, Ben N G; Kuipers, Jeroen; Miljkovic, Jan Lj; Mitrovic, Aleksandra; Bos, Eelke M.; Szabo, Csaba; Kampinga, Harm H.; Dijkers, Pascale F.; Den Dunnen, Wilfred F A; Filipovic, Milos R.; Van Goor, Harry; Sibon, Ody C M.

In: Molecular Medicine, Vol. 21, 24.08.2015, p. 758-768.

Research output: Contribution to journalArticle

Snijder, PM, Baratashvili, M, Grzeschik, NA, Leuvenink, HGD, Kuijpers, L, Huitema, S, Schaap, O, Giepmans, BNG, Kuipers, J, Miljkovic, JL, Mitrovic, A, Bos, EM, Szabo, C, Kampinga, HH, Dijkers, PF, Den Dunnen, WFA, Filipovic, MR, Van Goor, H & Sibon, OCM 2015, 'Overexpression of cystathionine γ-Lyase suppresses detrimental effects of spinocerebellar ataxia type 3', Molecular Medicine, vol. 21, pp. 758-768. https://doi.org/10.2119/molmed.2015.00221
Snijder PM, Baratashvili M, Grzeschik NA, Leuvenink HGD, Kuijpers L, Huitema S et al. Overexpression of cystathionine γ-Lyase suppresses detrimental effects of spinocerebellar ataxia type 3. Molecular Medicine. 2015 Aug 24;21:758-768. https://doi.org/10.2119/molmed.2015.00221
Snijder, Pauline M. ; Baratashvili, Madina ; Grzeschik, Nicola A. ; Leuvenink, Henri G D ; Kuijpers, Lucas ; Huitema, Sippie ; Schaap, Onno ; Giepmans, Ben N G ; Kuipers, Jeroen ; Miljkovic, Jan Lj ; Mitrovic, Aleksandra ; Bos, Eelke M. ; Szabo, Csaba ; Kampinga, Harm H. ; Dijkers, Pascale F. ; Den Dunnen, Wilfred F A ; Filipovic, Milos R. ; Van Goor, Harry ; Sibon, Ody C M. / Overexpression of cystathionine γ-Lyase suppresses detrimental effects of spinocerebellar ataxia type 3. In: Molecular Medicine. 2015 ; Vol. 21. pp. 758-768.
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