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Aging is not associated with proteasome impairment in UPS reporter mice.

ABSTRACT: Covalent linkage of ubiquitin regulates the function and, ultimately, the degradation of many proteins by the ubiquitin-proteasome system (UPS). Given its essential role in protein regulation, even slight perturbations in UPS activity can substantially impair cellular function.We have generated and characterized a novel transgenic mouse model which expresses a previously described reporter for UPS function. This UPS reporter contains a degron sequence attached to the C-terminus of green fluorescent protein, and is predominantly expressed in neurons throughout the brain of our transgenic model. We then demonstrated that this reporter system is sensitive to UPS inhibition in vivo.Given the obstacles associated with evaluating proteasomal function in the brain, our mouse model uniquely provides the capability to monitor UPS function in real time in individual neurons of a complex organism. Our novel mouse model now provides a useful resource with which to evaluate the impact of aging, as well as various genetic and/or pharmacological modifiers of neurodegenerative disease(s).

SUBMITTER: Cook C

PROVIDER: S-EPMC2690827 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Aging is not associated with proteasome impairment in UPS reporter mice.

Cook Casey C Gass Jennifer J Dunmore Judith J Tong Jimei J Taylor Julie J Eriksen Jason J McGowan Eileen E Lewis Jada J Johnston Jennifer J Petrucelli Leonard L

PloS one 20090611 6

<h4>Background</h4>Covalent linkage of ubiquitin regulates the function and, ultimately, the degradation of many proteins by the ubiquitin-proteasome system (UPS). Given its essential role in protein regulation, even slight perturbations in UPS activity can substantially impair cellular function.<h4>Methodology/principal findings</h4>We have generated and characterized a novel transgenic mouse model which expresses a previously described reporter for UPS function. This UPS reporter contains a de ...[more]

PMID: 19517018

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Project description:Toxocariasis is a worldwide zoonotic parasitic disease mainly caused by Toxocara canis. Humans can be infected by accidental ingestion of T. canis embryonated ovum-contaminated food, water, or encapsulated larvae in paratenic hosts' viscera or meat. Since humans and mice are paratenic hosts of T. canis, the wandering larvae might cause mechanical tissue damage and excretory-secretory antigens may trigger inflammatory injuries to local organs. Long-term residence of T. canis larvae in a paratenic host's brain may cause cerebral toxocariasis (CT) that contributes to cerebral damage, neuroinflammation and neuropsychiatric disorders in mice and clinical patients. Since the hippocampus has been long recognized as being responsible for learning and memory functions, parasitic invasion of this site may cause neuroinflammatory and neurodegenerative disorders. The present study intended to assess pathological changes, expressions of neurodegeneration-associated factors (NDAFs), including transforming growth factor (TGF)-?1, S100B, glial fibrillary acidic protein (GFAP), transglutaminase type 2 (TG2), claudin-5, substance P (SP) and interleukin (IL)-1?, and the ubiquitin-proteasome system (UPS) function in the hippocampus and associated cognitive behavior in ICR mice orally inoculated with a high, medium or low-dose of T. canis embryonated ova during a 20-week investigation.Results indicated although there were insignificant differences in learning and memory function between the experimental mice and uninfected control mice, possibly because the site where T. canis larvae invaded was the surrounding area but not the hippocampus per se. Nevertheless, enhanced expressions of NDAF, persistent UPS impairment and excess amyloid ? (A?) accumulation concomitantly emerged in the experimental mice hippocampus at 8, 16 and 20 weeks post-infection.We thus postulate that progressive CT may still progress to neurodegeneration due to enhanced NDAF expressions, persistent UPS impairment and excess A? accumulation in the hippocampus.

Dataset Information

Aging is not associated with proteasome impairment in UPS reporter mice.

Publications

Aging is not associated with proteasome impairment in UPS reporter mice.

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