The data herein show tissues with a decrease of RanBP2 and HKI levels mirror a reduction in the ATP levels. Since the constitutive Na+/K+ ATPase pump and the ATP-dependent conversion of glutamine to glutamate (both fundamental to maintain the electrical activity in the CNS) consumes the vast majority of the energy produced by the CNS [45–47], this likely underlies the suppression of the electrophysiological output responses of retinal neurons (Figure 8). Moreover, deficits in HKI may lead to intracellular hyperglycemia in the CNS, promote sorbitol-induced osmotic stress, and compromise further the ATPase-dependent Na+/K+ pump activity [48–50]. This may be exacerbated by a decrease of ATP, since the activity of HKI is also stimulated by ATP [51]. The cumulative effects of a reduction in ATP and intracellular hyperglycemia are known to act synergistically and modulate the electrophysiological properties of neuronal activity. Figure 9 integrates in a model these variables and implications of the data presented herein. Still, other bona fide RanBP2 partners previously identified and described in the Introduction also become strong candidates to play a role in energy homeostasis. For example, the unfolding and chaperone activity of components of the 19S cap of the proteasome may be modulated by the CLD of RanBP2 [14] and contribute to the selective HKI (and other substrates) degradation [43], while association of nuclear import receptor, importin-β with the Ran-binding domains of RanBP2 [10,11], may mediate the nuclear translocation of multifunctional substrates, such as glyceraldehyde-3-phosphate dehydrogenase. This trafficking process is selectively inhibited by the neuroprotective drug, R-(-)-deprenyl and derivates thereof, and are often employed to treat Parkinson disease [52–57]. Hence, RanBP2 and its partners emerge as key players and target genes in mediating neuropathophysiological mechanisms implicated in various genetic and environmental lesions to the CNS, as in patients with Parkinson, diabetes with insulin-resistance, and other neuropathies and neurodegenerative diseases, often linked to aging manifestations. To this effect, the RanBP2 mouse model will serve as a unique genetic tool to probe selective, multiple and novel pathways, which may have not been anticipated to be linked to metabolic processes and allied pathophysiological states.