The V81M variant of tyrosine hydroxylase is associated with more severe freezing of gait in Parkinson's disease

• We have shown a significant association between a common TH polymorphism and FOG in PD.
• The V81M mutation causes the doubling of the Michaelis–Menten constant for the enzyme's substrate; tyrosine.
• This supports a role for NE in the generation of FOG and supports a role of this system as a target for PD therapies.

IntroductionMany 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.MethodsWe 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.ResultsPD 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.ConclusionThe 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.