GIT2 Acts as a Potential Keystone Protein in Functional Hypothalamic Networks Associated with Age-Related Phenotypic Changes in Rats

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.

Nuclear GIT2 Is an ATM Substrate and Promotes DNA Repair

“…1k), indicating a potential strong trophic role of GIT2 in DNA repair. As we have previously demonstrated that GIT2 expression is sensitive to both aging and reactive oxygen species exposure (32,33), we postulated that GIT2 may also play a role in maintaining DNA stability during periods of stress.…”

“…Our previous findings demonstrated that GIT2 expression is elevated in the brains of multiple mammalian species with natural aging (32,33). As DNA damage can specifically accumulate in the central nervous system with aging, we next examined the effect of GIT2 genomic suppression upon DNA damage in the brains of elderly mice.…”

“…Recently, neuronal expression of GIT2 across multiple mammalian species has been shown to be modulated by oxidative stresses associated with the aging process (32). In addition, we have recently demonstrated that GIT2 acts as a functional keystone factor in aging-related physiological processes (33). As the aging process is closely linked to the stability/repair of DNA, we investigated the potential role of GIT2 in the DDR.…”

Proteome analysis in the assessment of ageing

“…Another interesting finding was the decrease in dynamin-1, a guanosine triphosphatase (Yang et al, 2008) that was also observed by VanGuilder et al (2010) in Fischer 344 × Brown Norway (F1) hybrid male rats (Chadwick et al, 2012;Freeman et al, 2009;Jiang et al, 2010) and Ottis et al (2013) in male outbred Wistar rats (Ottis et al, 2013). In the brain, dynamin-1 plays a pivotal role in the fission stage of synaptic vesicle endocytosis and thus neurotransmission (Ferguson et al, 2007) as well as in the mechanical stabilisation of F-actin bundles in growth cone fillipodia and thus growth cone motility and the elongation and guidance of axons to synaptic targets (Yamada et al, 2013).…”

Plurigon: three dimensional visualization and classification of high-dimensionality data

“…We therefore employed Plurigon to investigate and analogize the activity of AMI compared to endogenous classical neurotrophic peptides such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Transcriptomic responses to AMI (10 nM), BDNF (10 ng/mL) or NGF (10 ng/mL) stimulation (8 h) of SH-SY5Y cells were assessed as previously described (Martin et al, 2009; Chadwick et al, 2012). AMI-hydrochloride, BDNF and NGF were all obtained from Sigma Aldrich (St. Louis, MO).…”