We will examine the hypothesis that mutations in glutathione S- transferase (GST) isozymes influence onset age in Parkinson's disease (PD) caused by the PARK1 mutation. Environmental toxins some of which are degraded by GST-dependent pathways, have been implicated in the cause or onset age of PD. This work takes advantage of the PARK1 """"""""genetic model"""""""" of PD to seek insight into genetic and environmental bases for the wide variance in onset age of all PD. In 1997 our group and collaborators reported PARK1, a G209A nucleotide (A53T amino acid) substitution in alpha-synuclein at 4p21 in one Italian and two Greek families. Since then several other Greek families have been reported with PARK1 PD ranges from 22 to 86. Intraneuronal alpha-synuclein aggregation in the form of Lewy bodies occurs as the pathological hallmark of sporadic and mot familial PD, including PARK1 PD. Therefore, explaining the variation in onset age could lead to a means of usefully delaying the onset of all PD. We have preliminary data from 14 affected members of the Italian family (the """"""""Contursi kindred"""""""") showing a strong trend a relationship of younger onset age with homozygosity for the A313G allele of glutathione-S-transferase P1 (GST-P1) gene (p=0.51, Mann-Whitney rank sum test; p=.079, 2-sample t-test). We did not examine GST genes other than P1. We now propose to enlarge our N to at least 41 by adding samples from affected members of Greek PARK1 PD families.
Our Aims are to 1) Analyze our enlarged set of DNA samples for polymorphic alleles of GSTM1, -M3, -P1, -T1 and -Z1 and determine their effect, alone or in combination, on PD onset age; and 2) Assay GST activity in lymphoblasts from affected individuals to determine the functional significance of the mutations we may associated with PD onset age.
| Golbe, Lawrence I; Di Iorio, Giuseppe; Markopoulou, Katerina et al. (2007) Glutathione S-transferase polymorphisms and onset age in alpha-synuclein A53T mutant Parkinson's disease. Am J Med Genet B Neuropsychiatr Genet 144B:254-8 |
