Many components and pathways transducing multifaceted and deleterious effects of stress stimuli remain ill-defined. The Ran-binding protein 2 (RanBP2) interactome modulates the expression of a range of clinical and cell-context-dependent manifestations upon a variety of stressors. We examined the role of Ranbp2 haploinsufficiency on cellular and metabolic manifestations linked to tyrosine-hydroxylase (TH+) dopaminergic neurons and glial cells of the brain and retina upon acute challenge to 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), a parkinsonian neurotoxin, which models facets of Parkinson disease. MPTP led to stronger akinetic parkinsonism and slower recovery in Ranbp2+/- than wild-type mice without viability changes of brain TH+-neurons of either genotype, with the exception of transient nuclear atypia via changes in chromatin condensation of Ranbp2 +/- TH+-neurons. Conversely, the number of wild-type retinal TH+-amacrine neurons compared to Ranbp2+/- underwent milder declines without apoptosis followed by stronger recoveries without neurogenesis. These phenotypes were accompanied by a stronger rise of EdU+-proliferative cells and non-proliferative gliosis of GFAP?-Müller cells in wild-type than Ranbp2+/- that outlasted the MPTP-insult. Finally, MPTPtreated wild-type and Ranbp2+/- mice present distinct metabolic footprints in the brain or selective regions thereof, such as striatum, that are supportive of RanBP2-mediated regulation of interdependent metabolic pathways of lysine, cholesterol, free-fatty acids, or their β-oxidation. These studies demonstrate contrasting gene-environment phenodeviances and roles of Ranbp2 between dopaminergic and glial cells of the brain and retina upon oxidative stresselicited signaling and factors triggering a continuum of metabolic and cellular manifestations and proxies linked to oxidative stress, and chorioretinal and neurological disorders such as Parkinson.
Bibliographical noteFunding Information:
We thank Drs. F. Haeseleer (University of Washington) and D. Pow (University of Queensland) for the anti-CaBP5 and anti-GABA and anti-glycine antibodies, respectively. We thank Metabolon Inc. for providing a description of the mass spectrometry methodologies for specimen analyses. This work was supported by grants from the National Institutes of Health to PAF (EY019492, GM083165 and 2P30-EY005722) and Michael J. Fox Foundation. P.A.F. is the Jules & Doris Stein Research to Prevent Blindness Professor.
- Dopaminergic neurons
- Gene-environment interaction
- MPTP neurotoxicity
- Ran-binding protein 2 (RanBP2)