Identification of Glutathione S-Transferase Pi as a Protein Involved in Parkinson Disease Progression

Abstract

Parkinson disease (PD) typically affects the cortical regions during the later stages of disease, with neuronal loss, gliosis, and formation of diffuse cortical Lewy bodies in a significant portion of patients with dementia. To identify novel proteins involved in PD progression, we prepared synaptosomal fractions from the frontal cortices of pathologically verified PD patients at different stages along with age-matched controls. Protein expression profiles were compared using a robust quantitative proteomic technique. Approximately 100 proteins displayed significant differences in their relative abundances between PD patients at various stages and controls; three of these proteins were validated using independent techniques. One of the confirmed proteins, glutathione S-transferase Pi, was further investigated in cellular models of PD, demonstrating that its level was intimately associated with several critical cellular processes that are directly related to neurodegeneration in PD. These results have, for the first time, suggested that the levels of glutathione S-transferase Pi may play an important role in modulating the progression of PD.

Cocaine-Induced Adaptations in Cellular Redox Balance Contributes to Enduring Behavioral Plasticity

“…Interestingly, GSTpi is enriched in the striatum and dopamine neuron-containing regions of the ventral mesencephalon (Castro-Caldas et al, 2009). Accordingly, GSTP1P2-KO mice show an enhanced sensitivity to MPTPinduced dopamine depletion (Smeyne et al, 2007), and overexpression of three allelic GSTpi variants provides protection against rotenone-induced dopaminergic cell loss (Shi et al, 2009). In addition, human polymorphisms in GSTpi have been shown to increase susceptibility to Parkinson's disease (Vilar et al, 2007).…”

Exposure to pesticides and heterozygote genotype of GSTP1-Alw26I are associated to Parkinson's disease

“…The V/V homozygote did not show any association with PD, which was also reported by other authors 8,14 . The presence of the Val105 (V) allelic variant of GSTP1 is associated with the decrease of the enzyme activity, which would favor dopaminergic neurons degeneration in PD 4,15 . However, in this study, the wild genotype (I/I) presented association with familial PD.…”

“…Associations can be observed between GSTP1*B and sporadic PD 14 , especially in patients older than 69 years 4 . Additionally, Shi et al 15 indicated association of GSTP1 and PD when studying mice neuronal cells treated with neurotoxic substances. GSTP1*A prevented neuronal loss -contrary to GSTP1*B and GSTP1*C variants 15 .…”

“…Additionally, Shi et al 15 indicated association of GSTP1 and PD when studying mice neuronal cells treated with neurotoxic substances. GSTP1*A prevented neuronal loss -contrary to GSTP1*B and GSTP1*C variants 15 . In this context, single nucleotide studies in neurodegenerative diseases can contribute to feature gene-environmental interactions, especially with GSTP1 and PD, since it affects cellular response to toxicity and interferes in the penetrance of hereditary PD forms and the susceptibility to idiopathic PD.…”

“…The toxin is captured by dopamine and noradrenalin transporters and is accumulated in the cytosol, causing cellular death induced by oxidative stress and deficiency of the breathing mitochondrial chain 30 . Shi et al 15 demonstrated protection of the neuronal dopaminergic cells of mice exposed to rotenone by the expression of the wild GSTP1 (I allele), and reduced protection by its variants expression (V allele). These data were confirmed in the present study, by means of the association of GSTP1-Alw26I heterozygote, exposure to pesticides and PD.…”