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Immunoproteasome deficiency alters retinal proteasome's response to stress.

ABSTRACT: Our previous work demonstrated that immunoproteasome is up-regulated in the retina and brain in response to injury that does not involve an inflammatory response (J. Neurochem. 2008; 106:158). These results suggest additional non-immune functions for the immunoproteasome in the cellular stress response pathway. The present study further investigates the potential involvement of the immunoproteasome in responding to the chronic stress of aging or oxidant exposure in the retina and cultured retinal pigment epithelial (RPE) cells from knock-out mice missing either one (lmp7(-/-)) or two (lmp7(-/-)/mecl-1(-/-)) immunoproteasome subunits. We show that aging and chronic oxidative stress up-regulates immunoproteasome in the retina and RPE from wild-type mice. No up-regulation of LMP2 was observed in retinas or RPE lacking MECL-1 and/or LMP7, suggesting that the full complement of immunoproteasome subunits is required to achieve maximal up-regulation in response to stress. We also show that RPE deficient in immunoproteasome are more susceptible to oxidation-induced cell death, supporting a role for immunoproteasome in protecting from oxidative stress. These results provide key mechanistic insight into novel aspects of proteasome biology and are an important first step in identifying alternative roles for retinal immunoproteasome that are unrelated to its role in the immune response.

SUBMITTER: Hussong SA

PROVIDER: S-EPMC2909641 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Immunoproteasome deficiency alters retinal proteasome's response to stress.

Hussong Stacy A SA Kapphahn Rebecca J RJ Phillips Stacia L SL Maldonado Marcela M Ferrington Deborah A DA

Journal of neurochemistry 20100314 6

Our previous work demonstrated that immunoproteasome is up-regulated in the retina and brain in response to injury that does not involve an inflammatory response (J. Neurochem. 2008; 106:158). These results suggest additional non-immune functions for the immunoproteasome in the cellular stress response pathway. The present study further investigates the potential involvement of the immunoproteasome in responding to the chronic stress of aging or oxidant exposure in the retina and cultured retina ...[more]

PMID: 20345760

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Project description:Dysregulations of the central serotoninergic system have been implicated in several psychopathologies, characterized by different susceptibility between males and females. We took advantage of tryptophan hydroxylase 2 (TPH2) deficient rats, lacking serotonin specifically in the brain, to investigate whether a vulnerable genotype can be associated with alterations of neuronal plasticity from the early stage of maturation of the brain until adulthood. We found a significant increase, in both gene and protein expression, of the neurotrophin brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) of adult TPH2-deficient (TPH2-/-) male and female rats in comparison to wild type (TPH2+/+) counterparts. Interestingly, a development-specific pattern was observed during early postnatal life: whereas the increase in Bdnf expression, mainly driven by the modulation of Bdnf isoform IV was clearly visible after weaning at postnatal day (pnd) 30 in both sexes of TPH2-/- in comparison to TPH2+/+ rats, at early stages (pnd1 and pnd10) Bdnf expression levels did not differ between the genotypes, or even were downregulated in male TPH2-/- animals at pnd10. Moreover, to establish if hyposerotonergia may influence the response to a challenging situation, we exposed adult rats to an acute stress. Although the pattern of corticosterone release was similar between the genotypes, neuronal activation in response to stress, quantified by the expression of the immediate early genes activity regulated cytoskeleton associated protein (Arc) and Fos Proto-Oncogene (cFos), was blunted in both sexes of animals lacking brain serotonin. Interestingly, although upregulation of Bdnf mRNA levels after stress was observed in both genotypes, it was less pronounced in TPH2-/- in comparison to TPH2+/+ rats. In summary, our results demonstrated that serotonin deficiency affects neuroplastic mechanisms following a specific temporal pattern and influences the response to an acute stress.

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Immunoproteasome deficiency alters retinal proteasome's response to stress.

Publications

Immunoproteasome deficiency alters retinal proteasome's response to stress.

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