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GIT2 acts as a potential keystone protein in functional hypothalamic networks associated with age-related phenotypic changes in rats.

Chadwick W, Martin B, Chapter MC, Park SS, Wang L, Daimon CM, Brenneman R, Maudsley S - PLoS ONE (2012)

Bottom Line: However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood.Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration.Using novel combinatorial bioinformatics analyses, we were able to gain a better understanding of the proteomic and phenotypic changes that occur during the aging process and have potentially identified the G protein-coupled receptor/cytoskeletal-associated protein GIT2 as a vital integrator and modulator of the normal aging process.

View Article: PubMed Central - PubMed

Affiliation: Receptor Pharmacology Unit, Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Biomedical Research Center, Baltimore, Maryland, United States of America.

ABSTRACT
The aging process affects every tissue in the body and represents one of the most complicated and highly integrated inevitable physiological entities. The maintenance of good health during the aging process likely relies upon the coherent regulation of hormonal and neuronal communication between the central nervous system and the periphery. Evidence has demonstrated that the optimal regulation of energy usage in both these systems facilitates healthy aging. However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity. Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration. In this study, we examined alterations in protein expression in the hypothalami of young, middle-aged, and old rats. Using novel combinatorial bioinformatics analyses, we were able to gain a better understanding of the proteomic and phenotypic changes that occur during the aging process and have potentially identified the G protein-coupled receptor/cytoskeletal-associated protein GIT2 as a vital integrator and modulator of the normal aging process.

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Age-dependent protein expression changes in the rat hypothalamus.(A) Venn diagram analysis of significantly-regulated (p<0.05) proteins in the middle versus young (grey circle) and the old versus young (black circle) antibody array analyses. Proteins uniquely regulated in either middle age (22) or old age (64) animals are subsequently broken down into up-regulated (red numbers) or down-regulated (green numbers) groups. The 84 commonly-regulated proteins were further dissected into different regulatory-behavior groups represented in panels B–E. For each regulation-behavior group an exemplary protein is verified from the animal hypothalamic pools (Y–young, M–middle aged, O–old). (B) Proteins up-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with O ratio >M ratio. The associated validation was performed using western blot for caspase 3 (Casp3). (C) Proteins up-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with M ratio >O ratio. The associated validation was performed using western blot for Ran. (D) Proteins down-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with M ratio >O ratio and O ratio >M ratio. The associated validation was performed using western blot for vinculin (Vcl). (E) Proteins differentially regulated between M or O timepoints relative to Y (up-regulated at M and down-regulated at O (verified using junction plakoglobin-Jup), or down-regulated at M and up-regulated at O (verified using nitric oxide synthase 1-Nos)). For each verification, data on each histogram is represented as mean ± SEM from the multiple animal pools. Statistical significance is as follows: * = p<0.05, ** = p<0.01, *** = p<0.001.
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pone-0036975-g002: Age-dependent protein expression changes in the rat hypothalamus.(A) Venn diagram analysis of significantly-regulated (p<0.05) proteins in the middle versus young (grey circle) and the old versus young (black circle) antibody array analyses. Proteins uniquely regulated in either middle age (22) or old age (64) animals are subsequently broken down into up-regulated (red numbers) or down-regulated (green numbers) groups. The 84 commonly-regulated proteins were further dissected into different regulatory-behavior groups represented in panels B–E. For each regulation-behavior group an exemplary protein is verified from the animal hypothalamic pools (Y–young, M–middle aged, O–old). (B) Proteins up-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with O ratio >M ratio. The associated validation was performed using western blot for caspase 3 (Casp3). (C) Proteins up-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with M ratio >O ratio. The associated validation was performed using western blot for Ran. (D) Proteins down-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with M ratio >O ratio and O ratio >M ratio. The associated validation was performed using western blot for vinculin (Vcl). (E) Proteins differentially regulated between M or O timepoints relative to Y (up-regulated at M and down-regulated at O (verified using junction plakoglobin-Jup), or down-regulated at M and up-regulated at O (verified using nitric oxide synthase 1-Nos)). For each verification, data on each histogram is represented as mean ± SEM from the multiple animal pools. Statistical significance is as follows: * = p<0.05, ** = p<0.01, *** = p<0.001.

Mentions: With respect to the proteins differentially regulated between middle-aged or old animals and the young cohort, 84 proteins were found to be common between both M and O samples (Fig. 2A). In the middle-aged hypothalami there were 22 uniquely-regulated (not in O/Y) proteins (10 up-regulated, 12 down-regulated), while in the old animals there were 64 uniquely-regulated proteins (53 up-regulated, 11 down-regulated) (Fig. 2A). Among the 84 proteins commonly regulated in M/Y and O/Y, 53 proteins were similarly regulated (compared to Y animals), with 38 proteins up-regulated in M and O (Fig. 2B, C) and 15 proteins down-regulated in M and O (Figure 2D). We validated additional proteins for each of these protein subgroups: caspase 3 (Casp3, Fig. 2B), Ran (RAN, member RAS oncogene family, Fig. 2C) and vinculin (Vcl, Fig. 2D). In each of these western validations we recapitulated the expression trends observed with the antibody array (Table S3).


GIT2 acts as a potential keystone protein in functional hypothalamic networks associated with age-related phenotypic changes in rats.

Chadwick W, Martin B, Chapter MC, Park SS, Wang L, Daimon CM, Brenneman R, Maudsley S - PLoS ONE (2012)

Age-dependent protein expression changes in the rat hypothalamus.(A) Venn diagram analysis of significantly-regulated (p<0.05) proteins in the middle versus young (grey circle) and the old versus young (black circle) antibody array analyses. Proteins uniquely regulated in either middle age (22) or old age (64) animals are subsequently broken down into up-regulated (red numbers) or down-regulated (green numbers) groups. The 84 commonly-regulated proteins were further dissected into different regulatory-behavior groups represented in panels B–E. For each regulation-behavior group an exemplary protein is verified from the animal hypothalamic pools (Y–young, M–middle aged, O–old). (B) Proteins up-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with O ratio >M ratio. The associated validation was performed using western blot for caspase 3 (Casp3). (C) Proteins up-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with M ratio >O ratio. The associated validation was performed using western blot for Ran. (D) Proteins down-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with M ratio >O ratio and O ratio >M ratio. The associated validation was performed using western blot for vinculin (Vcl). (E) Proteins differentially regulated between M or O timepoints relative to Y (up-regulated at M and down-regulated at O (verified using junction plakoglobin-Jup), or down-regulated at M and up-regulated at O (verified using nitric oxide synthase 1-Nos)). For each verification, data on each histogram is represented as mean ± SEM from the multiple animal pools. Statistical significance is as follows: * = p<0.05, ** = p<0.01, *** = p<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351446&req=5

pone-0036975-g002: Age-dependent protein expression changes in the rat hypothalamus.(A) Venn diagram analysis of significantly-regulated (p<0.05) proteins in the middle versus young (grey circle) and the old versus young (black circle) antibody array analyses. Proteins uniquely regulated in either middle age (22) or old age (64) animals are subsequently broken down into up-regulated (red numbers) or down-regulated (green numbers) groups. The 84 commonly-regulated proteins were further dissected into different regulatory-behavior groups represented in panels B–E. For each regulation-behavior group an exemplary protein is verified from the animal hypothalamic pools (Y–young, M–middle aged, O–old). (B) Proteins up-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with O ratio >M ratio. The associated validation was performed using western blot for caspase 3 (Casp3). (C) Proteins up-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with M ratio >O ratio. The associated validation was performed using western blot for Ran. (D) Proteins down-regulated in both M (grey bars) and O (black bars) hypothalami compared to Y animals, with M ratio >O ratio and O ratio >M ratio. The associated validation was performed using western blot for vinculin (Vcl). (E) Proteins differentially regulated between M or O timepoints relative to Y (up-regulated at M and down-regulated at O (verified using junction plakoglobin-Jup), or down-regulated at M and up-regulated at O (verified using nitric oxide synthase 1-Nos)). For each verification, data on each histogram is represented as mean ± SEM from the multiple animal pools. Statistical significance is as follows: * = p<0.05, ** = p<0.01, *** = p<0.001.
Mentions: With respect to the proteins differentially regulated between middle-aged or old animals and the young cohort, 84 proteins were found to be common between both M and O samples (Fig. 2A). In the middle-aged hypothalami there were 22 uniquely-regulated (not in O/Y) proteins (10 up-regulated, 12 down-regulated), while in the old animals there were 64 uniquely-regulated proteins (53 up-regulated, 11 down-regulated) (Fig. 2A). Among the 84 proteins commonly regulated in M/Y and O/Y, 53 proteins were similarly regulated (compared to Y animals), with 38 proteins up-regulated in M and O (Fig. 2B, C) and 15 proteins down-regulated in M and O (Figure 2D). We validated additional proteins for each of these protein subgroups: caspase 3 (Casp3, Fig. 2B), Ran (RAN, member RAS oncogene family, Fig. 2C) and vinculin (Vcl, Fig. 2D). In each of these western validations we recapitulated the expression trends observed with the antibody array (Table S3).

Bottom Line: However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood.Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration.Using novel combinatorial bioinformatics analyses, we were able to gain a better understanding of the proteomic and phenotypic changes that occur during the aging process and have potentially identified the G protein-coupled receptor/cytoskeletal-associated protein GIT2 as a vital integrator and modulator of the normal aging process.

View Article: PubMed Central - PubMed

Affiliation: Receptor Pharmacology Unit, Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Biomedical Research Center, Baltimore, Maryland, United States of America.

ABSTRACT
The aging process affects every tissue in the body and represents one of the most complicated and highly integrated inevitable physiological entities. The maintenance of good health during the aging process likely relies upon the coherent regulation of hormonal and neuronal communication between the central nervous system and the periphery. Evidence has demonstrated that the optimal regulation of energy usage in both these systems facilitates healthy aging. However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity. Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration. In this study, we examined alterations in protein expression in the hypothalami of young, middle-aged, and old rats. Using novel combinatorial bioinformatics analyses, we were able to gain a better understanding of the proteomic and phenotypic changes that occur during the aging process and have potentially identified the G protein-coupled receptor/cytoskeletal-associated protein GIT2 as a vital integrator and modulator of the normal aging process.

Show MeSH
Related in: MedlinePlus