TY - JOUR
T1 - The V81M variant of tyrosine hydroxylase is associated with more severe freezing of gait in Parkinson's disease
AU - Tekin, Izel
AU - Carkaci-Salli, Nurgul
AU - Lewis, Mechelle M.
AU - Mailman, Richard B.
AU - Huang, Xuemei
AU - Vrana, Kent E.
N1 - Funding Information:
The authors thank Dr. Guangwei Du, Ms. Eleanore Hernandez, Ms. Brittany Jones, Ms. Melissa Santos, Ms. Grace Shyu and Ms. Raghda Clayiff for assistance with aspects of subject selection and Mr. Eugene Gonzales-Lopez for technical assistance. We also thank Ms. Christy Stetter for her assistance with statistical analyses. This work was supported by grants from the National Institutes of Health ( GM38931 , NIH NS060722 , NS082151 , Penn State Hershey Medical Center CTSI [ NIH UL1 TR000127 ], GCRC Construction [ C06 RR016499 ], and CTSI [ TL1 TR000125 ] research grants) and the Penn State Institute for Personalized Medicine ( 04-017-52 HY 8A1HO ; under a grant from the Pennsylvania Department of Health using Tobacco CURE Funds). The PA Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions.
Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
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U2 - 10.1016/j.parkreldis.2015.12.015
DO - 10.1016/j.parkreldis.2015.12.015
M3 - Article
C2 - 26732803
AN - SCOPUS:84951761106
VL - 23
SP - 86
EP - 90
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
SN - 1353-8020
ER -