The striatal dopaminergic deficit is dependent on the number of mutant alleles in a family with mutations in the parkin gene: Evidence for enzymatic parkin function in humans

Autosomal recessive parkinsonism associated with mutations in the parkin gene represents a monogenic form of hereditary parkinsonism. We performed [¹⁸F]6-fluorodopa (FDOPA) positron emission tomography as a measurement of the nigrostriatal dopaminergic system as well as extensive haplotype analysis of the PARK 2 gene locus in 14 subjects with parkin mutations. In parkin subjects, the reduction of striatal FDOPA uptake increased with the number of mutated alleles and was also slightly obvious in asymptomatic parkin gene carriers in the heterozygous state. The abnormal FDOPA uptake pattern in parkin patients did not significantly differ from that of sporadic Parkinson's disease. Our data are in agreement with an enzymatic dysfunction of the gene's translational product, which has been shown to promote protein degradation as an ubiquitin-protein ligase. Thus, parkinsonism in parkin gene carriers may be related to abnormal nigral protein accumulation in the presence of a suprathreshold enzyme dysfunction.