Ranbp2 haploinsufficiency mediates distinct cellular and biochemical phenotypes in brain and retinal dopaminergic and glia cells elicited by the Parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Thumbnail Image



Journal Title

Journal ISSN

Volume Title

Repository Usage Stats


Citation Stats


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, MPTP-treated 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 stress-elicited 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.





Published Version (Please cite this version)


Publication Info

Cho, Kyoung-In, Kelly Searle, Mason Webb, Haiqing Yi and Paulo A Ferreira (2012). Ranbp2 haploinsufficiency mediates distinct cellular and biochemical phenotypes in brain and retinal dopaminergic and glia cells elicited by the Parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cell Mol Life Sci, 69(20). pp. 3511–3527. 10.1007/s00018-012-1071-9 Retrieved from https://hdl.handle.net/10161/15580.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.



Paulo Alexandre Ferreira

Associate Professor in Ophthalmology

The long-term goal of our research program is twofold. The first is to understand the interplay between intracellular signaling, intracellular trafficking and proteostasis in health and disease; the second is to uncover molecular players and mechanisms partaking in such processes that are amenable to therapeutic intervention in a variety of disease states. Presently, our research efforts are centered on dissecting the roles of two disease-associated protein interactomes assembled by the Ran-binding protein 2 (RanBP2) and the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) in several neuronal cell types of the retina and brain that often undergo neurodegeneration upon a multiplicity of diseases with distinct etiologies.

The RanBP2 is a large and modular 358 kDa protein scaffold, which assembles a large multifunctional complex and acts a signal integrator of molecular and subcellular signaling and trafficking pathways critical to neuronal survival or function. Mutations or deficits in RanBP2 are linked to a variety of diseases processes ranging from neurodegeneration and necrosis to stress signaling and cancer. RanBP2 modulates the assembly or disassembly of several protein complexes with apparent disparate functions and implicated in molecular processes, such as nucleocytoplasmic and microtubule-based intracellular trafficking of proteins or organelles, protein homeostasis and biogenesis, modulation of protein-protein interactions (e.g. sumoylation), and control of cell division. Interdisciplinary approaches ranging from single molecule analysis to cell-based assays and genetically modified mouse models are employed to dissect selective cell type-dependent roles of proteins modulated dynamically by RanBP2 and underlying mechanisms in healthy and disease states.

The RPGRIP1 is also a modular protein, which associates directly with molecular partners, such as the retinitis pigmentosa GTPase regulator (RPGR) and nephrocystin-4 (NPHP4). Human mutations in the genes encoding RPGRIP1, RPGR and NPHP4 lead to severe ocular-renal, syndromic and non-syndromic retinal or renal diseases. These lead ultimately to blindness, loss of kidney function or both. Emerging data from our laboratory implicate the RPGRIP1 interactome in the regulation of the tethering, targeting, exiting and/or transport of selective retinal-renal and pre-ciliary components from the endoplasmic reticulum compartment to cilia. These processes serve as molecular determinants to the formation of subcellular structures/compartments that are critical to photoreceptor or tubular kidney cell functions . Current work is directed at dissecting: i) the biological and pathological roles of components of the RPGRIP1 interactome in retinal and kidney functions; ii) the molecular, cellular and pathophysiological bases of allelic-specific mutations and genetic heterogeneity affecting components of the RPGRIP1 interactome; iii) the identification of therapeutic targets and mechanisms dependent on the functions of the RPGRIP1 assembly complex and therapeutic approaches to delay the onset or progression of degeneration of photoreceptor, tubular kidney cells or both.

Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.