Alterations of STEP46 and STEP61 Expression in the Rat Retina with Age and AMD-Like Retinopathy Development

Abstract

Tyrosine phosphatase STEP (striatal-enriched tyrosine protein phosphatase) is a brain-specific protein phosphatase and is involved in the pathogenesis of many neurodegenerative diseases. Here, we examined the impact of STEP on the development of age-related macular degeneration (AMD)-like pathology in senescence-accelerated OXYS rats. Using OXYS and Wistar rats (control), we for the first time demonstrated age-dependent changes in Ptpn5 mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the retina. The increases in STEP protein levels and the decrease of total and STEP phosphatase activities in the retina (as compared with Wistar rats) preceded the manifestation of clinical signs of AMD in OXYS rats (age 20 days). There were no differences in these retinal parameters between 13-month-old Wistar rats and OXYS rats with pronounced signs of AMD. Inhibition of STEP with TC-2153 during progressive AMD-like retinopathy (from 9 to 13 months of age) reduced the thickness of the retinal inner nuclear layer, as evidenced by a decreased amount of parvalbumin-positive amacrine neurons. Prolonged treatment with TC-2153 had no effect on Ptpn5 mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the OXYS retina. Thus, TC-2153 may negatively affect the retina through mechanisms unrelated to STEP.

Ambiguous Effects of Prolonged Dietary Supplementation with a Striatal-Enriched Protein Tyrosine Phosphatase Inhibitor, TC-2153, on a Rat Model of Sporadic Alzheimer’s Disease

“…At the same time, we did not note any differences in these retinal parameters between 13-month-old Wistar rats and OXYS rats (the latter show pronounced signs of AMD). Moreover, inhibition of STEP with TC-2153 at the same age and duration as in the present study (from 9 to 13 months of age) has a negative effect on the neuroretina while having no influence on Ptpn5 mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the OXYS retina [35]. Those results, just as the data obtained in the present study, suggest that the effects of prolonged treatment with TC-2153 may be mediated by mechanisms not related to STEP.…”

“…Indeed, prolonged administration of TC-2153 here improved long-term memory of OXYS rats while significantly reducing the already decreased locomotor and exploratory activities and increasing their anxiety: the alterations that we consider a manifestation of accelerated senescence of these rats' brain. An even more alarming result of long-term treatment with TC-2153 may be its negative influence on retinal neurons, as we reported previously [35]. Thus, prolonged administration of TC-2153 may exert longitudinal actions on redox status by altering an oxidation and reduction balance.…”

“…This disorder shares several clinical and histopathological features with AD, and some researchers regard AMD as AD of the eye [36]. Recently, we showed [35] that an increase in the STEP61 protein level and a decrease in total and STEP phosphatase activities in the retina (as compared with Wistar rats) precede the manifestation of clinical signs of AMD in OXYS rats (age 20 days). At the same time, we did not note any differences in these retinal parameters between 13-month-old Wistar rats and OXYS rats (the latter show pronounced signs of AMD).…”

“…According to Jian Xu and co-workers [5], TC-2153 inhibits STEP activity by forming a covalent bond with active-site Cys472, which is required for the enzymatic activity, without changing the amount of total STEP and phosphorylated STEP. In the present study, we did not examine the activity and phosphorylation of STEP61 but evaluated them when investigating the effects of TC-2153 on the retina of OXYS rats [35]. AD-like pathology develops in OXYS rats simultaneously with other manifestations of accelerated senescence, one of which is retinopathy, similar to age-related macular degeneration (AMD) in humans [21].…”