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)
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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.
KeywordsRan-binding protein 2 (RanBP2) MPTP neurotoxicity Dopaminergic neurons Gliosis Metabolomics Parkinson Gene–environment interaction
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that models multiple facets of Parkinson’s disease (PD) [1, 2, 3, 4]. 1-methyl-4-phenylpyridinium (MPP+) is the active metabolite of MPTP that is taken up by dopaminergic neurons , where it is thought to poison these by inhibition of the mitochondrial complex I and generation of superoxide anions [6, 7]. Previous experiments with mesencephalic neuronal cultures also supported that MPTP could promote the displacement of dopamine from vesicular stores, leading then to the intracellular and extracellular auto-oxidation of dopamine and production of reactive oxygen species (ROS) . The pathophysiological relevance of these results are controversial, because (i) dopaminergic neurons (DA) of mice lacking functional Ndufs4, a subunit critical to the functional assembly of complex I, are not protected to MPP+  and (ii) acute administration of MPTP still induces neurotoxicity in DA neurons of DA-deficient mice , whereas overexpression of the dopamine transporter in striatal neurons of transgenic mice lent support to the concept that impairment of intracellular dopamine vesicular sequestration suffices to promote neurodegeneration . In addition to DA neuronal degeneration, MPTP is also reported to induce gliosis and microglial activation, events that are thought to contribute to the injury of DA neurons [12, 13]. The effects of MPTP and comparison of its pathophysiological outcomes become more complex with the observations that rodents are more resistant to MPTP neurotoxicity than primates and the multivariate susceptibilities to MPTP treatment vary significantly with mouse strains, sex, age, and treatment modalities [12, 14, 15, 16, 17, 18, 19, 20].
The neuroretina also harbors TH+-amacrine neurons. These DA neurons are the least numerous and the largest neurons in the retina because of the large arborization fields they present [21, 22]. Dopamine plays a role in light adaptation and PD patients suffer from various visual impairments [23, 24]. MPTP treatment is also reported to reduce reversibly or have no effect on the number of DA amacrine neurons and these effects are accompanied by a decrease of the retinal oscillatory potentials and activation of glial and microglial cells and astrocytes [25, 26, 27, 28, 29, 30]. Hence, collectively these results support that the multifaceted and cell-context-dependent responses elicited by the Parkinsonian neurotoxin, MPTP, are susceptible to modulation by ill-characterized factors. Identification and characterization of such biological factors are of considerable therapeutic value, because among other reasons they may uncover disease-relevant pathways and serve as pharmacological targets to promote neuroprotection.
The Ran-binding protein 2 (RanBP2) is known to modulate directly responses elicited by various deleterious stressors, such as phototoxicity [31, 32], infectious agents , and carcinogens . In this regard, haploinsufficiency of Ranbp2 confers neuroprotection to photoreceptor neurons upon light-elicited oxidative stress [31, 32], whereas semi-dominant mutations in human RANBP2 promote the rampant necrosis of basal ganglia neurons triggered by febrile states and viral infections of multiple etiologies . Additionally, haploinsufficiency or hypomorphism of Ranbp2 increases the susceptibility to tumorigenesis in the presence of carcinogens . Parkin, whose loss-of-function causes PD in the human, is reported to associate with RanBP2 . Like Ranbp2, parkin (PARK2) is also a tumor-suppressor gene . Parkin and RanBP2 exhibit E3-ubiquitin ligase activity and the association of parkin with RanBP2 promotes the ubiquitination and degradation of RanBP2 [35, 37, 38]. Among other locations, RanBP2 and parkin appear to localize to the mitochondria, where parkin is thought to exert a neuroprotective role [39, 40, 41, 42]. parkin −/− mice present deficits in lipid and glucose metabolism and energy homeostasis [42, 43], a phenotype that evokes manifestations observed with haploinsufficiency of Ranbp2 [31, 40]. Hence, these data collectively support that RanBP2 modulates stress signaling pathways critical to neuronal viability and that RanBP2 and parkin may share pathomechanisms of relevance to the survival or function of dopaminergic neurons. To further define the role of deficits in RanBP2 in stress-mediated responses, we explored in this study the role of haploinsufficiency of Ranbp2 in brain and retinal tyrosine-hydroxylase (TH+)-neurons and glial cells upon acute exposure to the Parkinsonian neurotoxin, MPTP, in an inbred mouse strain (129P2/OlaHsd). We found significant multifaceted phenotypic and metabolic footprint manifestations in the brain and retina between inbred wild-type and Ranbp2 +/− mice. These phenotypic outcomes may underlie phenodeviances and pathobiological processes shared by diseases linked to oxidative stress, including parkinsonian manifestations.
Materials and methods
Mice and drug administration
Animal protocols were approved by the Institutional Animal Care and Use Committee at Duke University and the procedures adhered to the ARVO guidelines for the Use of Animals in Vision Research and National Academy of Sciences. Twenty-four to 28-week-old wild-type or Ranbp2 +/− (Ranbp2 +/Gt(pGT0pfs)630Wcs ) male mice previously generated with an identical inbred 129P2/OlaHsd genetic background were employed . Mice were housed in a temperature-controlled and pathogen-free transgenic barrier facility in a standard 12:12 h light–dark cycle at <70 lux and given ad libitum access to water and breeder chow diet 5LJ5 (Purina). Mice received four bolus i.p. injections of MPTP.HCl (20 mg/kg, Sigma) in physiological saline at 2-h intervals and the first injection was administered 9:00–10:00 a.m. Mice were kept in isolation until being killed. For these studies, all mice were killed by cervical dislocation followed by decapitation at either 6 or 14 days after MPTP treatment.
Mice were transferred separately to a 46 × 42 cm Plexiglas box with the bottom marked with a 25-square grid. Mice motility was recorded daily in isolation for 15 min; data were analyzed by counting the number of quadrants each mouse traveled within a constant time period.
EdU administration, labeling, and staining
For cumulative EdU (5-ethynyl-2′-deoxyuridine, Invitrogen) labeling , mice received a daily bolus of EdU by i.p. injection (100 μl of 1 mg ml−1 EdU) during the first 6 or 13 days immediately following the last MPTP bolus or from days 9 to 13 after MPTP treatment. Mice were killed at days 6 or 14 after MPTP treatment. Development of EdU staining was performed always after incubation of sections or flatmounts with primary antibodies against cell markers and secondary antibodies. After incubation with the secondary antibody, brain and retinal sections or retinal flatmounts were fixed with 4 % paraformaldehyde in PBS solution for 15 min, washed once with 3 % BSA in 100 mM PBS, followed by permeabilization with 100 mM PBS, pH 7.4/0.5 % Triton X-100 for 20 min. Finally, specimens were incubated with the EdU detection cocktail for 30 min as per the manufacturer’s instructions (Click-iT® EdU Alexa 488 Imaging Kit, Invitrogen, Carlsbad, CA, USA).
List of primary and secondary antibodies are described in Supplementary Materials and Methods.
Tissue collection for morphological and morphometric analyses
Collection, processing, and immunostaining of brain and retina specimens for morphometric analyses are described in detail in Supplementary Materials and Methods.
Free-floating 50-μm coronal sections of selected brain regions, 12-μm frozen retinal sections mounted on slides or flat-mount retinas were incubated in blocking buffer (PBS, pH 7.4, containing 0.1 % Triton X-100, 10 % normal goat serum) at room temperature for 1 h followed by an incubation with primary antibody in incubation buffer (PBS, pH 7.4, containing 0.1 % Triton X-100, 5 % normal goat serum) overnight at room temperature (brain) or 4 °C (retina). After three times of washing with washing buffer (PBS with 0.1 % Triton X-100) for 10 min, specimens were incubated in incubation buffer for 2 h with one or more Alexa-conjugated secondary antibody (1:1,000; Invitrogen, Carlsbad). Specimens were washed three times with washing buffer and whenever applicable mounted on glass slides for visualization and image acquisition with a Nikon 90i C1 Plus confocal microscope.
Detection of apoptosis was carried out in situ in brain and retinal sections with the DeadEnd Fluorimetric TUNEL System (Promega) exactly as described elsewhere .
Unbiased metabolomic profiling of whole brains of wild-type and Ranbp2 +/− mice 6 days after MPTP treatment was performed by Metabolon, Inc. (Durham, NC). Brains were immediately stored at −80 °C after dissection and upon discarding the olfactory bulb and cerebellum. The brains were then provided to Metabolon, Inc. Additional metabolomic methodologies employed by Metabolon are described in Supplementary Materials and Methods.
Immediately after the mice were killed, tissues were collected, snap frozen in liquid nitrogen, and stored at −80 °C in a freezer. Liver, midbrain, and striatum tissue extracts in 250 μl of NP-40 were prepared using Precellys® 24 dual tissue homogenizer (Bertin Technologies, Montignyle-Bretonneux), at 6,000 rpm for 23 s. Total cholesterol, free cholesterol, and esterified cholesterol were measured as previously described . Levels of Coenzyme A were determined by the Coenzyme A Assay Kit (Biovision, Mountain View, CA, USA) as directed by the manufacturer. Results were normalized against protein amounts in NP40 tissue extracts used for each assay. Two-sample t test statistical analyses with the assumption of unequal variance were performed; p ≤ 0.05 was defined as significant.
Haploinsufficiency of Ranbp2 causes increased akinesia and slow recovery upon MPTP treatment
MPTP promotes transient nuclear atypia in brain TH+-neurons of Ranbp2 +/− mice
MPTP promotes distinct effects between TH+-neurons and GFAP+-glia in retinae of wild-type and Ranbp2 +/− mice
Haploinsufficiency of Ranbp2 suppresses the proliferation of EdU+-cells in the retina that do not regenerate into TH+-amacrine neurons upon MPTP treatment
We then examined the identity of the EdU+- cells, whose proliferation was suppressed in Ranbp2 +/− mice upon MPTP treatment, with antibodies against antigens known to be either expressed in retinal progenitor cells or markers up-regulated in proliferating cells upon retinal injury. In particular, Sox2 is known to be required for differentiation of progenitor cells to amacrine and other retinal neurons , whereas GFAP, CD45, and CD11b are markers for Müller glia and astrocytes, vascular (leukocytes), and resting and activated microglia and macrophages, respectively [48, 49, 50]. GFAP+-, CD45+-, and CD11b+-cells are known to proliferate upon retinal damage to various stress stimuli [50, 51, 52]. As shown in Fig. 7c–f, most cellular markers tested were expressed in EdU− cells, albeit with some differences. Among the GFAP+ cells, only very few were EdU+, thus supporting GFAP+-cells represent a small fraction of EdU+-proliferating cells (Fig. 7c). In the retina, all CD45+ were EdU− (Fig. 7d) and the few CD45+EdU+ identified in several sections were exclusively localized in the choroid plexus (Fig. 7e). All CD11b+ cells identified were EdU−cells and they appeared to be macrophages that were also exclusively localized in the choroid plexus (Supplementary Fig. 2). Finally, we did not identify EdU+-Sox2 cells (Fig. 7f). Hence, the majority of the EdU+-cells in the retina represents cells of novel origin or identity.
Ranbp2-dependent metabolic imbalances in the brain upon exposure to acute MPTP treatment
The second subset comprises a significant rise in Ranbp2 +/− mice of the levels of several carnitine conjugates, such as 3-dehydrocarnitine (1.6-fold) and glutaroyl carnitine (1.87-fold), and a trend for an increase in propionylcarnitine (1.55-fold). These surges are also accompanied by an increase of 2-aminoadipate (2.13-fold), an intermediate in lysine metabolism. The rise of the metabolites of this group is likely due to an increase of lysine catabolism, because of increases in the levels of 2-aminoadipate, 3-dehydrocarnitine, and glutaroyl carnitine. Further, odd-chain acylcarnitines, such as propionylcarnitine (C3), are produced during amino acid catabolism . Interestingly, we found the levels of several other acylcarnitines, such as butyrylcarnitine, acetylcarnitine, palmitoylcarnitine, stearoylcarnitine, and oleoylcarnitine, to be elevated in Ranbp2 +/− mice. The changes in these acylcarnitines levels represented some of the greatest fold increases of this study (from 1.55- to over threefold) and there was a significant correlation between their elevated levels in Ranbp2 +/− mice (r s > 0.9; p < 0.037) even though the differences of the mean levels of each between genotypes were not significant. Acylcarnitines transport long-chain and medium-chain fatty acids into the mitochondria for energy generation via β-oxidation and together with reduced levels of coenzyme A, they likely contribute to the accumulation of acylcarnitines .
Finally, the last subgroup is characterized by significant increases of glycerophosphorylcholine (1.48-fold), glucose (1.76-fold), lactate (1.36-fold), nicotinamide adenine dinucleotide (NAD+) (1.45-fold), and dehydroascorbate (2.1-fold). These changes are accompanied also by increased trends of the levels of glycerol 3-phosphate (1.54-fold), myo-inositol (1.22-fold), and threonate (1.78-fold). Altogether, the accumulation of these metabolites may arise from an impairment of the glycerophosphate shunt and reduced anaplerosis of the Krebs cycle . Glycerophosphorylcholine and myo-inositol are also cellular osmolytes with important roles in maintaining cellular volume in response to hypertonic stress .
The rise in lysine catabolism in Ranbp2 +/− mice also correlates directly with changes in a second group of metabolites, 1-methylimidazoleacetate (t-MIAA; 1.43-fold) and homocarnosine/γ-aminobutyryl-l-histidine (0.81-fold) (Figs. 8, 9b). The significant increase of the former results from the enhanced catabolism of histidine to histamine and it is a reliable marker of histamine turnover rate  and such augmented conversion likely induces a decrease of the levels of the dipeptide homocarnosine . This dipeptide is formed from γ-aminobutyric acid (GABA) and histidine, and it is found mostly in the brain, where it may act as a GABA reservoir, the main neurotransmitter inhibitor of the brain. Notably, the immediate precursor of t-MIAA, methylimidazole acetaldehyde, is the metabolite of the oxidative deamination of N-methylhistamine by the monoamine oxidase type B (MAO-B), which also metabolizes dopamine upon its oxidative deamination and converts MPTP to MPP+. MAO-B is also a therapeutic target for Parkinson’s disease.
The third group reflects a rise of metabolites of the methionine and adenine salvage pathways in Ranbp2 +/− mice (Figs. 8, 9c). There was a significant 1.4-fold increase of adenine that was accompanied by strong trends of a rise of the levels of 5-methylthioadenosine (1.32-fold) and xanthosine (1.32-fold). Finally, the fourth and fifth groups are represented by the metabolites, reduced glutathione (GSH) (0.65-fold) and ophthalmate (1.47-fold), and hippurate (0.59-fold), respectively (Figs. 8, 9d, e). Ophthalmate and hippurate metabolites arise from the conjugation reactions with glycine. Hippurate is a common metabolite of detoxification reactions . Ophthalmate is a tripeptide analogue of glutathione and a useful biomarker of redox state and oxidative damage of tissues when it is accompanied typically by depletion of reduced glutathione (GSH) . We found that lower levels of GSH were accompanied by a trend of higher levels of ophthalmate. Further, it is of interest to note that the glutathione cycle is also coupled with the GABA shunt (synthesis of γ-aminobutyrate) , thus changes in the levels of metabolites of glutathione cycle are likely to contribute to compound biochemical phenotypes.
The data support that a difference in genetic dosage of Ranbp2 in the inbred 129P2/OlaHsd genetic background modulates significant metabolic pathways in the brain without causing significant nigrostriatal cellular changes upon acute MPTP exposure. In contrast, a variety of cell types of the retina undergo significant cellular changes upon Ranbp2 haploinsufficiency and MPTP exposure with the most striking effects observed by the suppression of the following cellular manifestations: (i) gliosis of GFAP+-Müller cells outlasting the xenobiotic insult, (ii) recovery of TH+-amacrine neurons and (iii) activation of a heterogeneous population of proliferative cells across the retina. This study also uncovers a distinct and large proliferative population of cells elicited by MPTP that differ from those reported for other neurotoxicity models, such as intraocular injection of N-methyl-D-aspartic acid (NMDA) with or without selective growth factors, glutamate, or α-aminoadipate [65, 66, 67]. NMDA together with retinoic acid induces the regeneration of a restricted number of Müller cells into bipolar or photoreceptor cells, whereas NMDA in the presence of EGF, FGF1, or FGF1 combined with insulin, stimulates the production of Müller glia with a small fraction of these regenerating into undefined amacrine neurons [65, 66]. However, glutamate or α-aminoadipate, which was found in this study to be significantly elevated in Ranbp2 +/−, promotes the transient proliferation of Müller glial cells and differentiation into retinal neurons, such as photoreceptors . By contrast, our study found that MPTP elicits long-lasting retinal gliosis by dramatically up-regulating resident GFAP+-Müller cells without the majority of these cells undergoing proliferation. Further, we did not identify any MPTP-elicited EdU+-proliferating cells with the capacity to regenerate into TH+-amacrine neurons even though most were localized to the inner retina. Instead, MPTP promotes the transient suppression of TH expression in dopaminergic amacrine neurons followed by marked and compensatory recoveries of TH expression in such neurons, a finding that is consistent with the work reported by Tatton et al. . Hence, the data imply the existence of distinct cellular and molecular responses to MPTP-neurotoxicity between TH+-neurons of the brain and the retina. These data support the existence of distinct TH+-neuronal subtypes between these tissues and RanBP2- and microenvironment-dependent trophic signaling between unique populations of MPTP-activated and proliferative glia in the brain and retina.
These data also support the existence of a novel population of EdU+-proliferating cells elicited by MPTP and repressed by Ranbp2 haploinsufficiency. In contrast to other inflammatory models of neurotoxicity and injury to the retina [50, 51, 52, 68], the EdU+-proliferating cells elicited by MPTP and resident in the retina were neither CD45+ nor CD11b+ and the former cells were never detected in retinas of Ranbp2 +/− mice. Instead, CD45+EdU− and CD45+EdU+ cells were only detected in the choroid (vascular) plexus of Ranbp2 +/− mice, whereas CD11b+ cells were exclusively present in the choroid plexus and they were all EdU−. Altogether, these data strengthen the notion of the development of distinct and antagonistic phenotypic outcomes observed between cell types by Ranbp2 insufficiency upon other disease stressors, such as phototoxicity [31, 32] and carcinogen exposure . For example, the increased carcinogen-induced cellular proliferation (e.g., tumorigenesis) upon Ranbp2 insufficiency contrasts sharply with the suppression of the MPTP-induced proliferative capacity of progenitor cells in the retina of Ranbp2 +/− mice as uncovered by this study. These differences are likely caused by the deregulation of the Ranbp2-mediated nucleocytoplasmic shuttling of factors or receptors thereof controlling cell proliferation or differentiation [69, 70, 71, 72, 73]. One of such factors is the Ranbp2 partner, Ubc9, which is an E2-ligase implicated in the shuttling and homeostasis of some orphan receptors [32, 74, 75, 76, 77, 78]. It is noteworthy that Ubc9 mediates the repression of pro-inflammatory responses in microglia and astrocytes by Nurr1 , which is associated with familial late-onset PD .
Our studies also reveal metabolic imbalances in the brain caused by haploinsufficiency of Ranbp2 upon acute exposure to MPTP. The metabolic footprint uncovered is significant, because it not only validates and opens new venues to the identity of some undefined and possibly shared metabolites modulated by other stressors, such as phototoxicity [31, 32], but it also delineates disease and diagnostic predictors of metabolic pathways with relevance to the understanding of complex clinical and subclinical phenotypes of human diseases caused by interactions between the environment and Ranbp2.
In this regard, this study defines the identity of two medium-chains (pelargonate and caprate) and a long-chain fatty acid species (arachidate/eicosanoic acid), whose decreased levels are associated with haploinsufficiency of Ranbp2. Interestingly, the level of arachidate increases upon inflammation [81, 82] and as such, its decrease in Ranbp2 +/− upon MPTP treatment may contribute to the suppression of inflammatory cellular responses observed in the retina of Ranbp2 +/− mice. Further, the modulation of pro-inflammatory responses linked to insufficiency of RanBP2 is likely mediated by the concerted action of multiple metabolites. 5-methylthioadenosine and α-aminoadipate, which are increased in Ranbp2 +/− mice, are additional metabolites with important anti-inflammatory or anti-proliferative properties, or both [67, 83, 84].
This work also identifies a set of metabolites from metabolic pathways, which are apparently distinct, and are known to either produce biomarkers of oxidative stress or present secondary and protective properties against toxic or injury insults of other etiologies. For example, l-propionyl carnitine is associated with a reduction in lipid hydroperoxides and superoxide anions and the propionyl moiety of l-propionyl carnitine provides intermediates to the TCA cycle upon stress conditions and contributes to its therapeutic benefits . Homocarnosine and 5-methylthioadenosine are also known to be protective against oxidative stress with the former acting also as a scavenger for reactive oxygen species [61, 83]. The increase of these metabolites is accompanied by disruption of redox homeostasis as reflected by an increase of diagnostic markers of oxidative stress, such as dehydroascorbate and ophthalmate, with the latter acting as biomarker of glutathione depletion . Our data support that the rise of such “protective” metabolites likely represents secondary and compensatory responses and diagnostic markers to noxious insults and that insufficiency of RanBP2 confers an increased susceptibility to such neurotoxic damage in the brain.
Finally, the accumulation of various acyl-carnitines, glucose, lactic acid, and NAD+ support a detoxifying efflux from the mitochondria of metabolites derived from the incomplete β-oxidation of free fatty acids concomitant with enhanced anaerobic glycolysis. Current knowledge supports that these imbalances arise likely from the glia, because neurons are thought not to utilize β-oxidation of free fatty acids as energy source . These bioenergetic manifestations assume heightened relevance to our studies, because MPP+ is thought to inhibit directly the NADH:ubiquinone oxidoreductase of Complex I of the electron transport chain of the mitochondria [6, 7] and the decrease of the levels of CoA observed selectively in the striatum of Ranbp2 +/− mice may contribute to the incomplete β-oxidation of free fatty acids in this brain region. It is not exactly clear how partial deficits of RanBP2 exacerbate certain bioenergetic facets of neurotoxic stress-induced manifestations. However, the work of Neilson et al. and ours support that the down-regulation of hexokinase I activity by deficits of RanBP2  or stimulation of the uncoupling of state IV of oxidative phosphorylation by mutations in Ranbp2 upon infectious agents and febrile states [33, 86] may espouse a predilection for higher glucose levels and enhanced anaerobic glycolysis upon insufficiency of RanBP2 and exposure to a variety of stressors.
Collectively, these and other data point toward a number of RanBP2-mediated metabolic and neurodegenerative diseases of acute and insidious clinical expressions sharing strong gene-environment interactions and broader spectra of metabolic footprints and pathomechanisms than hitherto realized. For example, PD and acute encephalopathies often result in striatal injury, but differ by the onset or progression of injury. Familial necrotic encephalopathies caused by mutations in RANBP2 and a number of other encephalopathies of cerebral organic acid origin are often precipitated by episodes of febrile and infectious illnesses, which in turn may elicit fasting and catabolic stress, and secondarily, excitotoxic, and proinflammatory mechanisms [33, 87, 88]. Like other acute encephalopathies, infectious agents may also act as novel etiological agents in Parkinson disease [89, 90] and systemic metabolic deficits can directly promote dramatic clinical manifestations with distinct onsets and selective tissue expressions, such as age-dependent chorioretinal degenerations (e.g., gyrate atrophy) [91, 92], and once thought not to share pathomechanisms. In this regard, our findings strengthen the view that mouse models of Ranbp2 are tractable genetic and physiological tools for the discovery of pathobiological mechanisms underlying diseases triggered by gene-environment interactions.
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.
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- 5.Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 82:2173–2177CrossRefPubMedGoogle Scholar
- 18.Fornai F, Schluter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, Pellegrini A, Nicoletti F, Ruggieri S, Paparelli A, Sudhof TC (2005) Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci USA 102:3413–3418CrossRefPubMedGoogle Scholar
- 20.Hamre K, Tharp R, Poon K, Xiong X, Smeyne RJ (1999) Differential strain susceptibility following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration acts in an autosomal dominant fashion: quantitative analysis in seven strains of Mus musculus. Brain Res 828:91–103CrossRefPubMedGoogle Scholar
- 32.Cho KI, Yi H, Tserentsoodol N, Searle K, Ferreira PA (2010) Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress. Dis Model Mech 3:595–604CrossRefPubMedGoogle Scholar
- 33.Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr DS, Anderson J, Bassuk AG, Bye AM, Childs AM, Clarke A, Crow YJ, Di Rocco M, Dohna-Schwake C, Dueckers G, Fasano AE, Gika AD, Gionnis D, Gorman MP, Grattan-Smith PJ, Hackenberg A, Kuster A, Lentschig MG, Lopez-Laso E, Marco EJ, Mastroyianni S, Perrier J, Schmitt-Mechelke T, Servidei S, Skardoutsou A, Uldall P, van der Knaap MS, Goglin KC, Tefft DL, Aubin C, de Jager P, Hafler D, Warman ML (2009) Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet 84:44–51CrossRefPubMedGoogle Scholar
- 36.Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, Janakiraman M, Schultz N, Hanrahan AJ, Pao W, Ladanyi M, Sander C, Heguy A, Holland EC, Paty PB, Mischel PS, Liau L, Cloughesy TF, Mellinghoff IK, Solit DB, Chan TA (2010) Somatic mutations of the Parkinson’s disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet 42:77–82CrossRefPubMedGoogle Scholar
- 43.Kim KY, Stevens MV, Akter MH, Rusk SE, Huang RJ, Cohen A, Noguchi A, Springer D, Bocharov AV, Eggerman TL, Suen DF, Youle RJ, Amar M, Remaley AT, Sack MN (2011) Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells. J Clin Invest 121:3701–3712CrossRefPubMedGoogle Scholar
- 51.Nakazawa T, Hisatomi T, Nakazawa C, Noda K, Maruyama K, She H, Matsubara A, Miyahara S, Nakao S, Yin Y, Benowitz L, Hafezi-Moghadam A, Miller JW (2007) Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis. Proc Natl Acad Sci USA 104:2425–2430CrossRefPubMedGoogle Scholar
- 61.De Marchis S, Modena C, Peretto P, Migheli A, Margolis FL, Fasolo A (2000) Carnosine-related dipeptides in neurons and glia. Biochemistry (Mosc) 65:824–833Google Scholar
- 63.Soga T, Baran R, Suematsu M, Ueno Y, Ikeda S, Sakurakawa T, Kakazu Y, Ishikawa T, Robert M, Nishioka T, Tomita M (2006) Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption. J Biol Chem 281:16768–16776CrossRefPubMedGoogle Scholar
- 78.Kurihara I, Shibata H, Kobayashi S, Suda N, Ikeda Y, Yokota K, Murai A, Saito I, Rainey WE, Saruta T (2005) Ubc9 and protein inhibitor of activated STAT 1 activate chicken ovalbumin upstream promoter-transcription factor I-mediated human CYP11B2 gene transcription. J Biol Chem 280:6721–6730CrossRefPubMedGoogle Scholar
- 82.Boyd JD, Jang H, Shepherd KR, Faherty C, Slack S, Jiao Y, Smeyne RJ (2007) Response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) differs in mouse strains and reveals a divergence in JNK signaling and COX-2 induction prior to loss of neurons in the substantia nigra pars compacta. Brain Res 1175:107–116CrossRefPubMedGoogle Scholar
- 85.Speijer D (2010) Oxygen radicals shaping evolution: why fatty acid catabolism leads to peroxisomes while neurons do without it: FADH/NADH flux ratios determining mitochondrial radical formation were crucial for the eukaryotic invention of peroxisomes and catabolic tissue differentiation. BioEssays 33:88–94CrossRefGoogle Scholar