Izel Tekin1, Nurgul Carkaci-Salli1, Mechelle M Lewis2, Richard B Mailman2, Xuemei Huang3, Kent E Vrana4. 1. Department of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA. 2. Department of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA; Department of Neurology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA. 3. Department of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA; Department of Neurology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA; Departments of Radiology and Neurosurgery, Milton S. Hershey Medical Center, and Kinesiology, Pennsylvania State University, Hershey, PA, USA. 4. Department of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA. Electronic address: kvrana@psu.edu.
Abstract
INTRODUCTION: Many of the symptoms and signs of Parkinson's disease (PD) arise from the death of midbrain dopamine neurons that utilize tyrosine hydroxylase (TH) as the rate-limiting enzyme in catecholamine biosynthesis. METHODS: We investigated whether the presence of a common TH polymorphism affects the clinical outcomes in 101 PD subjects. We further examined the effect of this polymorphism on the purified recombinant enzyme. RESULTS: PD subjects homozygous for the common V81M polymorphism, have higher overall freezing of gait scores after controlling for disease duration, although this polymorphism does not associate with the occurrence of PD or FOG. In vitro functional assays on pure recombinant wild type TH and V81M TH revealed that the Km of the mutant enzyme for tyrosine was twice that of the wild-type. This polymorphism, however, did not change the stability of the enzyme, nor did it affect the Vmax or Km for the co-substrate BH4. CONCLUSION: The data suggest that presence of a homozygous V81M polymorphism is associated with more severe FOG, possibly due to lower catecholamine synthetic capacity. Further studies are warranted to investigate the role of subtle changes in catecholamine availability in the development of FOG.
INTRODUCTION: Many of the symptoms and signs of Parkinson's disease (PD) arise from the death of midbrain dopamine neurons that utilize tyrosine hydroxylase (TH) as the rate-limiting enzyme in catecholamine biosynthesis. METHODS: We investigated whether the presence of a common TH polymorphism affects the clinical outcomes in 101 PD subjects. We further examined the effect of this polymorphism on the purified recombinant enzyme. RESULTS:PD subjects homozygous for the common V81M polymorphism, have higher overall freezing of gait scores after controlling for disease duration, although this polymorphism does not associate with the occurrence of PD or FOG. In vitro functional assays on pure recombinant wild type TH and V81MTH revealed that the Km of the mutant enzyme for tyrosine was twice that of the wild-type. This polymorphism, however, did not change the stability of the enzyme, nor did it affect the Vmax or Km for the co-substrate BH4. CONCLUSION: The data suggest that presence of a homozygous V81M polymorphism is associated with more severe FOG, possibly due to lower catecholamine synthetic capacity. Further studies are warranted to investigate the role of subtle changes in catecholamine availability in the development of FOG.
Authors: Nurgul Carkaci-Salli; John M Flanagan; Matthew K Martz; Ugur Salli; Diego J Walther; Michael Bader; Kent E Vrana Journal: J Biol Chem Date: 2006-07-24 Impact factor: 5.157
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