Gene expression and gene association studies for sepiapterin reductase and microtubule-associated protein tau in familial Parkinson's disease

Parkinson's disease (PD) is a common adult-onset neurodegenerative disorder affecting close to 2% of the population over the age of 65. While mutations in a handful of genes have been implicated in a subset of familial PD cases, chromosomal loci that have shown linkage and association to PD, including PARK3 and chromosome 17q21, are still under investigation. One of the candidate genes at the PARK3 locus is sepiapterin reductase ( SPR), which catalyzes the final step of the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor in the synthesis of dopamine. The expression of SPR and other enzymes involved in BH4 biosynthesis was evaluated using real-time RT-PCR in human post-mortem cerebellar tissue from 32 individuals with neuropathologically-confirmed PD and 28 neurologically normal controls. SPR expression was significantly increased in PD cases relative to controls, while the expression of aldose reductase and 6-pyruvoyltetrahydrobiopterin synthase was significantly decreased in PD cases. Single-nucleotide polymorphisms (SNPs) around SPR did not have a significant effect on SPR mRNA expression. The relative abundance of sepiapterin reductase (SR) protein was not different between PD cases and controls using a western blot. SR immunoreactivity in the cortex, striatum and substantia nigra in 5 PD cases was similar to that reported in normal brain. Microtubule-associated protein tau (MAPT ) on chromosome l7q21 has been associated with several forms of parkinsonism, including PD. The association of MAPT SNPs and haplotypes to PD was evaluated in the GenePD Study and expression of 4-repeat and 3-repeat MAPT isoforms and two nearby genes, Saitohin (STH) and KIAA1267 was evaluated. The minor allele at rs1800547 was significantly protective for PD in an additive genetic model. While the widely studied H1 haplotype was significantly associated with an increased risk for PD, a novel haplotype was identified, which showed a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA127 was significantly increased in PD brains relative to controls. Collectively these studies support roles for SPR and MAPT, and possibly STH and KIAA1267 in the pathogenesis of some forms of idiopathic PD.