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

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2015
2253.pdf (4.744Mb)
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)
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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.

Source:
Molecular Medicine, 2015, 21, 758-768
Publisher:
  • 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
[ Google Scholar ]
29
20
URI
https://cherry.chem.bg.ac.rs/handle/123456789/2255
Collections
  • Publikacije / Publications
Institution/Community
Hemijski fakultet / Faculty of Chemistry
TY  - 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 . .

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