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

2015
Authors
Snijder, Pauline M.Baratashvili, Madina
Grzeschik, Nicola A.
Leuvenink, Henri G. D.
Kuijpers, Lucas
Huitema, Sippie
Schaap, Onno
Giepmans, Ben N. G.
Kuipers, Jeroen
Miljković, Jan Lj
Mitrović, Aleksandra D.

Bos, Eelke M.
Szabo, Csaba
Kampinga, Harm H.

Dijkers, Pascale F.
den Dunnen, Wilfred F. A.
Filipović, Miloš R.

van Goor, Harry
Sibon, Ody C. M.
Article (Published version)
Metadata
Show full item recordAbstract
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.-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.-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.-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine.-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine.-lyase expression or activity are attractive candidates for future therapies.
Source:
Molecular Medicine, 2015, 21, 758-768Publisher:
- Feinstein Inst Med Res, Manhasset
Funding / projects:
- ZonMW [91111.006]
- Jan Kornelis de Cock Foundation
- VICI grant
Note:
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3402
DOI: 10.2119/molmed.2015.00221
ISSN: 1076-1551
PubMed: 26467707
WoS: 000377271200009
Scopus: 2-s2.0-84975138044
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Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Snijder, Pauline M. AU - Baratashvili, Madina AU - Grzeschik, Nicola A. AU - Leuvenink, Henri G. D. AU - Kuijpers, Lucas AU - Huitema, Sippie AU - Schaap, Onno AU - Giepmans, Ben N. G. AU - Kuipers, Jeroen AU - Miljković, Jan Lj AU - Mitrović, Aleksandra D. AU - Bos, Eelke M. AU - Szabo, Csaba AU - Kampinga, Harm H. AU - Dijkers, Pascale F. AU - den Dunnen, Wilfred F. A. AU - Filipović, Miloš R. AU - van Goor, Harry AU - Sibon, Ody C. M. PY - 2015 UR - https://cherry.chem.bg.ac.rs/handle/123456789/2255 AB - 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.-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.-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.-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine.-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine.-lyase expression or activity are attractive candidates for future therapies. PB - Feinstein Inst Med Res, Manhasset T2 - Molecular Medicine T1 - Overexpression of Cystathionine gamma-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3 VL - 21 SP - 758 EP - 768 DO - 10.2119/molmed.2015.00221 ER -
@article{ author = "Snijder, Pauline M. and Baratashvili, Madina and Grzeschik, Nicola A. and Leuvenink, Henri G. D. and Kuijpers, Lucas and Huitema, Sippie and Schaap, Onno and Giepmans, Ben N. G. and Kuipers, Jeroen and Miljković, Jan Lj and Mitrović, Aleksandra D. and Bos, Eelke M. and Szabo, Csaba and Kampinga, Harm H. and Dijkers, Pascale F. and den Dunnen, Wilfred F. A. and Filipović, Miloš R. and van Goor, Harry and Sibon, Ody C. M.", year = "2015", 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.-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.-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.-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine.-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine.-lyase expression or activity are attractive candidates for future therapies.", publisher = "Feinstein Inst Med Res, Manhasset", journal = "Molecular Medicine", title = "Overexpression of Cystathionine gamma-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3", volume = "21", pages = "758-768", doi = "10.2119/molmed.2015.00221" }
Snijder, P. M., Baratashvili, M., Grzeschik, N. A., Leuvenink, H. G. D., Kuijpers, L., Huitema, S., Schaap, O., Giepmans, B. N. G., Kuipers, J., Miljković, J. L., Mitrović, A. D., Bos, E. M., Szabo, C., Kampinga, H. H., Dijkers, P. F., den Dunnen, W. F. A., Filipović, M. R., van Goor, H.,& Sibon, O. C. M.. (2015). Overexpression of Cystathionine gamma-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3. in Molecular Medicine Feinstein Inst Med Res, Manhasset., 21, 758-768. https://doi.org/10.2119/molmed.2015.00221
Snijder PM, Baratashvili M, Grzeschik NA, Leuvenink HGD, Kuijpers L, Huitema S, Schaap O, Giepmans BNG, Kuipers J, Miljković JL, Mitrović AD, Bos EM, Szabo C, Kampinga HH, Dijkers PF, den Dunnen WFA, Filipović MR, van Goor H, Sibon OCM. Overexpression of Cystathionine gamma-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3. in Molecular Medicine. 2015;21:758-768. doi: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, Miljković, Jan Lj, Mitrović, Aleksandra D., Bos, Eelke M., Szabo, Csaba, Kampinga, Harm H., Dijkers, Pascale F., den Dunnen, Wilfred F. A., Filipović, Miloš R., van Goor, Harry, Sibon, Ody C. M., "Overexpression of Cystathionine gamma-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3" in Molecular Medicine, 21 (2015):758-768, https://doi.org/10.2119/molmed.2015.00221 . .