Exp Neurobiol.  2010 Jun;19(1):23-29. 10.5607/en.2010.19.1.23.

Inactivation of Aconitase by Tetrahydrobiopterin in DArgic Cells: Relevance to PD

• Yoon NS
• Cho Y
• Lee SY
• Choi HJ
• Hwang O

• KMID: 2165316
• DOI: http://doi.org/10.5607/en.2010.19.1.23

Abstract

Oxidative damage is thought to be a major cause of the progression of dopamine (DA)rgic neurodegeneration as in Parkinson's disease. We have previously reported that tetrahydrobiopterin (BH4), an endogenous molecule required for DA synthesis, exerts oxidative stress to DA-producing cells and facilitates the production of DA quinone. It is known that aconitase, present in both mitochondrial and cytosolic forms, act as an reactive oxygen species (ROS) sensor, and that their inactivation leads to further generation of ROS. In the present study we investigated whether the BH4-associated vulnerability of DA cells might involve aconitase. In DArgic cell line CATH.a, BH4 treatment caused reduction of activity of both mitochondrial and cytosolic aconitases, and this appeared to be due to direct inactivation of the pre-existing enzyme molecules. Although most of the activity reduced by BH4 was increased upon reactivation reaction under a reducing condition, the restoration was not complete, suggesting that irreversible and covalent modification has occurred. The aconitase inactivation was exacerbated in the presence of DA and attenuated in the presence of tyrosine hydroxylase inhibitor a-methyl-p-tyrosine, suggesting the involvement of DA. The degree of inactivation increased when the cells were treated with the quinone reductase inhibitor dicoumarol and decreased in the presence of quinone reductase inducer sulforaphane. Taken together, BH4 appeared to lead to both reversible and irreversible inactivation of aconitase and that this is facilitated by the presence of DA and accumulation of DA quinone.

Keyword

aconitase; tetrahydrobiopterin; dopamine quinone; oxidative stress

MeSH Terms

Aconitate Hydratase
Benzoquinones
Biopterin
Cell Line
Cytosol
Dicumarol
Dopamine
NAD(P)H Dehydrogenase (Quinone)
Oxidative Stress
Parkinson Disease
Reactive Oxygen Species
Thiocyanates
Tyrosine 3-Monooxygenase
Aconitate Hydratase
Benzoquinones
Biopterin
Dicumarol
Dopamine
NAD(P)H Dehydrogenase (Quinone)
Reactive Oxygen Species
Thiocyanates
Tyrosine 3-Monooxygenase