Title

FK506-Binding Protein 12.6/1b, a Negative Regulator of [Ca<sup>2+</sup>], Rescues Memory and Restores Genomic Regulation in the Hippocampus of Aging Rats.

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Volume

38

Issue

None

Pages

1030-1041

Date

2018-01-24

Authors

Blalock EM | Chen KC | Gant JC | Kadish I | Landfield PW | Porter NM | Thibault O

Genes in the mTOR pathway were also of specific interest because this pathway is inhibited by the immunosuppressant drug rapamy- cin via complex formation with FKBP1b/1a.

Nevertheless, the lack of change in mTOR pathway gene expression suggests that FKBP1b’s genomic effects were not mediated by the mTOR pathway.

MAP2: downregulation with aging and restoration by FKBP1b

Cpn-1 (calpain-1) and Ppp3cc (calcineurin, Nixon et al., 1994; Rozkalne et al., 2011; Furman and Norris, 2014), as well as a Ca2􏰅 release-activated Ca2􏰅 channel (ORAI1) were altered by aging and restored by FKBP1b treatment (Table 3).

Moreover, FKBP1a, a close isoform of FKBP1b, negatively regulates mTOR in the brain, even in the absence of rapamycin

FKBP1b overexpression improved spatial reference and reversal memory for both LT and ST aged groups

Remarkably, only four of the 876 aging-dependent and FKBP1b- sensitive genes (Eif3g, Pla2g7, S100􏰌, and Snapc2) exhibited exac- erbation of aging effects by FKBP1b, whereas the other 872 changed in opposite directions with aging and FKBP1b treatment.

Genes downregulated with aging and upregulated by FKBP1b (AC downregulated vs YC, FKBP1b upregulated vs AC, template II) strongly overrepresented GO categories related to intracellular and extracellular structure, including: cytoskeleton, extracellular region passive transmembrane transporter activity, ectoderm devel- opment, regulation of actin cytoskeleton organization, and regulation of MAP kinase activity (Table 1)

Genes upregulated with aging and downregulated by FKBP1b (AC upregulated vs YC, FKBP1b downregulated vs AC, template IV) overrepresented GO category annotations related to extracel- lular remodeling and transporter activity, including extracellular matrix, primary transmembrane transporter activity, blood vessel development, regulation of cell motion, and membrane-bounded vesicle (Table 1)

Because FKBP1b is a negative regulator of hippocampal neuronal Ca2􏰅 transients

Twenty-four mTOR pathway genes were identified by searching the GO data- base and the literature (Johnson et al., 2013). Of these 24, only two, Hif1an and Nfkb1, were significantly altered with both age (upregulated) and FKBP1b (downregulated), showing that the mTOR pathway was not statistically overrepresented by FKBP1b- sensitive genes (n.s., p 􏰆 0.78, binomial test).

AAV-FKBP1b injection increased hippocampal FKBP1b protein and gene expression, particularly in the LT group

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.