Abstract
The multifunctional E3 ubiquitin ligase CHIP is an essential interacting partner of HSP70, which together promote the proteasomal degradation of client proteins. Acute CHIP overexpression provides neuroprotection against neurotoxic mitochondrial stress, glucocorticoids, and accumulation of toxic amyloid fragments, as well as genetic mutations in other E3 ligases, which have been shown to result in familial Parkinson's disease. These studies have created a great deal of interest in understanding CHIP activity, expression and modulation. While CHIP knockout mice have the potential to provide essential insights into the molecular control of cell fate and survival, the animals have been difficult to characterize in vivo due to severe phenotypic and behavioral dysfunction, which have thus far been poorly characterized. Therefore, in the present study we conducted a battery of neurobehavioral and physiological assays of adult CHIP heterozygotic (HET) mutant mice to provide a better understanding of the functional consequence of CHIP deficiency. We found that CHIP HET mice had normal body and brain weight, body temperature, muscle tone and breathing patterns, but do have a significant elevation in baseline heart rate. Meanwhile basic behavioral screens of sensory, motor, emotional and cognitive functions were normative. We observed no alterations in performance in the elevated plus maze, light-dark preference and tail suspension assays, or two simple cognitive tasks: novel object recognition and spontaneous alternation in a Y maze. Significant deficits were found, however, when CHIP HET mice performed wire hang, inverted screen, wire maneuver, and open field tasks. Taken together, our data indicate a clear subset of behaviors that are altered at baseline in CHIP deficient animals, which will further guide whole animal studies of the effects of CHIP dysregulation on cardiac function, brain circuitry and function, and responsiveness to environmental and cellular stress.
Highlights
Heat shock proteins (HSPs) are highly conserved, abundantly expressed chaperone proteins with diverse functions, including the assembly of multi-protein complexes, transport of nascent polypeptides, regulation of protein folding, and neuroprotection [1]
Heat shock protein 70 (HSP70) operates as part of a multi-protein complex in which associated co-chaperone molecules can alter client proteins bound to HSP70 thereby affecting the trafficking, degradation and refolding activities of HSP70 [5,6,7]
Animals and General Behavioral Methods CHIP heterozygous and wild type littermate mice were bred in house from matings of heterozygous to wild type mice, and weaned at postnatal day (P) 21 at which time genotypes were determined by PCR analysis of tail tissue using standard procedures [18,19]
Summary
Heat shock proteins (HSPs) are highly conserved, abundantly expressed chaperone proteins with diverse functions, including the assembly of multi-protein complexes, transport of nascent polypeptides, regulation of protein folding, and neuroprotection [1]. CHIP is a central modulator of both the activity and expression of HSP70 as it interacts with the chaperone and promotes its degradation [8]. Loss of CHIP might result in increased susceptibility to stress and increased cell death due to a dysregulation of essential client proteins. Overexpression of CHIP can decrease central nervous system cell death in models of chronic neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease [11,15,16]. Recently shown that CHIP can affect essential signaling pathways and be deleterious to cellular health when chronically overexpressed [17], suggesting a delicate balance must exist to promote cell survival
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