The Experts below are selected from a list of 228 Experts worldwide ranked by ideXlab platform
Rehana K. Leak - One of the best experts on this subject based on the ideXlab platform.
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Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
2016Co-Authors: Jessica M. Posimo, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:In Parkinson’s and Alzheimer’s diseases, the Allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and Allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in Allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in Allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in Allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as Allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered Allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middl
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Heat shock protein defenses in the neocortex and Allocortex of the telencephalon
Neurobiology of aging, 2015Co-Authors: Jessica M. Posimo, Justin N. Weilnau, Amanda M. Gleixner, Matthew T. Broeren, Nicole L. Weiland, Jeffrey L. Brodsky, Peter Wipf, Rehana K. LeakAbstract:The telencephalic Allocortex develops protein inclusions before the neocortex in many age-related proteinopathies. One major defense mechanism against proteinopathic stress is the heat shock protein (Hsp) network. We therefore contrasted Hsp defenses in stressed primary neocortical and allocortical cells. Neocortical neurons were more resistant to the proteasome inhibitor MG132 than neurons from 3 allocortical subregions: entorhinal cortex, piriform cortex, and hippocampus. However, allocortical neurons exhibited higher MG132-induced increases in Hsp70 and heat shock cognate 70 (Hsc70). MG132-treated allocortical neurons also exhibited greater levels of protein ubiquitination. Inhibition of Hsp70/Hsc70 activity synergistically exacerbated MG132 toxicity in allocortical neurons more than neocortical neurons, suggesting that the Allocortex is more reliant on these Hsp defenses. In contrast, astrocytes harvested from the neocortex or Allocortex did not differ in their response to Hsp70/Hsc70 inhibition. Consistent with the idea that chaperones are maximally engaged in allocortical neurons, an increase in Hsp70/Hsc70 activity was protective only in neocortical neurons. Finally, the levels of select Hsps were altered in the neocortex and Allocortex in vivo with aging.
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Correction: Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
PLoS ONE, 2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:There were multiple errors in the Author Contributions statement. The Author Contributions statement should read: "Conceived and designed the experiments: RKL. Performed the experiments: JMP AMT. Analyzed the data: JMP AMT HJHC ASU. Wrote the paper: RKL."
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Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
PloS one, 2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:In Parkinson’s and Alzheimer’s diseases, the Allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and Allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in Allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in Allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in Allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as Allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered Allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middle age. PA28 levels rose with age and were higher in Allocortex in vivo, also paralleling in vitro data. These neo- and allocortical differences have implications for the many studies that treat the telencephalic mantle as a single unit. Our observations suggest that the topographic progression of protein aggregations through the cerebrum may reflect differential responses to low level protein-misfolding stress but also reveal impressive compensatory adaptations in Allocortex.
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Impact of natural aging on neocortex and Allocortex in vivo.
2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:A: Glutathione levels in whole tissue lysates of rat neo- and Allocortex as a function of age. Allocortical glutathione levels were similar to those in neocortex but rose in an age-dependent manner and were significantly higher at 19–22 months of age relative to the youngest group (2–4 months). Neocortical glutathione did not change significantly as a function of age. B–C: Western immunoblotting for ceruloplasmin as a function of age and brain region. Neocortex had much more ceruloplasmin than Allocortex at every age examined. Furthermore, neocortical ceruloplasmin rose in an age-dependent manner until rats were 16–19 months old. D–E: PA28 levels as a function of age in neo- and Allocortex. PA28 levels rose in neocortex at 19–22 months and in Allocortex at 16–19 months relative to the youngest age group. Allocortical PA28 levels were significantly higher than in neocortex at 16–19 months of age. Data are expressed as mean and standard error of the mean from 4–5 rats per group. For all panels, **p ≤ 0.01, ***p ≤ 0.001, Allocortex versus neocortex;+p ≤ 0.05,+++p ≤ 0.001 versus levels in the 2–4 month old group; Bonferroni post hoc correction following two-way ANOVA.
Jessica M. Posimo - One of the best experts on this subject based on the ideXlab platform.
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Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
2016Co-Authors: Jessica M. Posimo, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:In Parkinson’s and Alzheimer’s diseases, the Allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and Allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in Allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in Allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in Allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as Allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered Allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middl
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Heat shock protein defenses in the neocortex and Allocortex of the telencephalon
Neurobiology of aging, 2015Co-Authors: Jessica M. Posimo, Justin N. Weilnau, Amanda M. Gleixner, Matthew T. Broeren, Nicole L. Weiland, Jeffrey L. Brodsky, Peter Wipf, Rehana K. LeakAbstract:The telencephalic Allocortex develops protein inclusions before the neocortex in many age-related proteinopathies. One major defense mechanism against proteinopathic stress is the heat shock protein (Hsp) network. We therefore contrasted Hsp defenses in stressed primary neocortical and allocortical cells. Neocortical neurons were more resistant to the proteasome inhibitor MG132 than neurons from 3 allocortical subregions: entorhinal cortex, piriform cortex, and hippocampus. However, allocortical neurons exhibited higher MG132-induced increases in Hsp70 and heat shock cognate 70 (Hsc70). MG132-treated allocortical neurons also exhibited greater levels of protein ubiquitination. Inhibition of Hsp70/Hsc70 activity synergistically exacerbated MG132 toxicity in allocortical neurons more than neocortical neurons, suggesting that the Allocortex is more reliant on these Hsp defenses. In contrast, astrocytes harvested from the neocortex or Allocortex did not differ in their response to Hsp70/Hsc70 inhibition. Consistent with the idea that chaperones are maximally engaged in allocortical neurons, an increase in Hsp70/Hsc70 activity was protective only in neocortical neurons. Finally, the levels of select Hsps were altered in the neocortex and Allocortex in vivo with aging.
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Correction: Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
PLoS ONE, 2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:There were multiple errors in the Author Contributions statement. The Author Contributions statement should read: "Conceived and designed the experiments: RKL. Performed the experiments: JMP AMT. Analyzed the data: JMP AMT HJHC ASU. Wrote the paper: RKL."
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Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
PloS one, 2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:In Parkinson’s and Alzheimer’s diseases, the Allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and Allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in Allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in Allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in Allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as Allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered Allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middle age. PA28 levels rose with age and were higher in Allocortex in vivo, also paralleling in vitro data. These neo- and allocortical differences have implications for the many studies that treat the telencephalic mantle as a single unit. Our observations suggest that the topographic progression of protein aggregations through the cerebrum may reflect differential responses to low level protein-misfolding stress but also reveal impressive compensatory adaptations in Allocortex.
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Impact of natural aging on neocortex and Allocortex in vivo.
2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:A: Glutathione levels in whole tissue lysates of rat neo- and Allocortex as a function of age. Allocortical glutathione levels were similar to those in neocortex but rose in an age-dependent manner and were significantly higher at 19–22 months of age relative to the youngest group (2–4 months). Neocortical glutathione did not change significantly as a function of age. B–C: Western immunoblotting for ceruloplasmin as a function of age and brain region. Neocortex had much more ceruloplasmin than Allocortex at every age examined. Furthermore, neocortical ceruloplasmin rose in an age-dependent manner until rats were 16–19 months old. D–E: PA28 levels as a function of age in neo- and Allocortex. PA28 levels rose in neocortex at 19–22 months and in Allocortex at 16–19 months relative to the youngest age group. Allocortical PA28 levels were significantly higher than in neocortex at 16–19 months of age. Data are expressed as mean and standard error of the mean from 4–5 rats per group. For all panels, **p ≤ 0.01, ***p ≤ 0.001, Allocortex versus neocortex;+p ≤ 0.05,+++p ≤ 0.001 versus levels in the 2–4 month old group; Bonferroni post hoc correction following two-way ANOVA.
Roger L. Reep - One of the best experts on this subject based on the ideXlab platform.
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Manatee cerebral cortex: cytoarchitecture of the caudal region in Trichechus manatus latirostris.
Brain behavior and evolution, 1995Co-Authors: C D Marshall, Roger L. ReepAbstract:In several brains of the Florida manatee, Trichechus manatus latirostris, the architecture of caudal regions of cerebral cortex was examined in order to complete a map of cortical areas in the brain of this unique herbivore. Through observation of sections stained for Nissl substance, myelinated axons, acetylcholinesterase and cytochrome oxidase, we have identified 11 new cortical areas based on qualitative cytoarchitectural appearance and measurements of laminar thicknesses, for a total of 24 such cortical areas in manatee cerebral cortex. Some areas exhibit poorly differentiated laminae while in others there are 6 clearly demarcated layers, often with sublaminar organization. Some previously identified areas were found to extend into the region caudal to the vertically oriented lateral fissure. As in other mammalian brains, cortical areas in manatees are organized in concentric rings of Allocortex, mesocortex, and isocortex. Putative functional roles have been assigned to most of the identified areas based on location, architecture, behavioral and anatomical considerations, and extrapolation from other taxa in which functional mapping has been done.
Ajay S. Unnithan - One of the best experts on this subject based on the ideXlab platform.
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Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
2016Co-Authors: Jessica M. Posimo, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:In Parkinson’s and Alzheimer’s diseases, the Allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and Allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in Allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in Allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in Allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as Allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered Allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middl
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Correction: Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
PLoS ONE, 2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:There were multiple errors in the Author Contributions statement. The Author Contributions statement should read: "Conceived and designed the experiments: RKL. Performed the experiments: JMP AMT. Analyzed the data: JMP AMT HJHC ASU. Wrote the paper: RKL."
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Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
PloS one, 2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:In Parkinson’s and Alzheimer’s diseases, the Allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and Allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in Allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in Allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in Allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as Allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered Allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middle age. PA28 levels rose with age and were higher in Allocortex in vivo, also paralleling in vitro data. These neo- and allocortical differences have implications for the many studies that treat the telencephalic mantle as a single unit. Our observations suggest that the topographic progression of protein aggregations through the cerebrum may reflect differential responses to low level protein-misfolding stress but also reveal impressive compensatory adaptations in Allocortex.
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Impact of natural aging on neocortex and Allocortex in vivo.
2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:A: Glutathione levels in whole tissue lysates of rat neo- and Allocortex as a function of age. Allocortical glutathione levels were similar to those in neocortex but rose in an age-dependent manner and were significantly higher at 19–22 months of age relative to the youngest group (2–4 months). Neocortical glutathione did not change significantly as a function of age. B–C: Western immunoblotting for ceruloplasmin as a function of age and brain region. Neocortex had much more ceruloplasmin than Allocortex at every age examined. Furthermore, neocortical ceruloplasmin rose in an age-dependent manner until rats were 16–19 months old. D–E: PA28 levels as a function of age in neo- and Allocortex. PA28 levels rose in neocortex at 19–22 months and in Allocortex at 16–19 months relative to the youngest age group. Allocortical PA28 levels were significantly higher than in neocortex at 16–19 months of age. Data are expressed as mean and standard error of the mean from 4–5 rats per group. For all panels, **p ≤ 0.01, ***p ≤ 0.001, Allocortex versus neocortex;+p ≤ 0.05,+++p ≤ 0.001 versus levels in the 2–4 month old group; Bonferroni post hoc correction following two-way ANOVA.
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Involvement of autophagic defenses and ubiquitin-proteasome system.
2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:A–B: Infrared Western immunoblotting for macroautophagy-related molecule Beclin 1 following treatment of neo- and allocortical cultures with 0.25 and 1 µM MG132 is shown. β-actin was used as a loading control. C–D: Ammonium chloride (20 mM NH4Cl) was used to inhibit all forms of autophagy and wortmannin (50 nM) was used to inhibit macroautophagy in neo- and allocortical cultures subjected to vehicle or 0.25 µM MG132. Neocortical neurons became as vulnerable to MG132 as allocortical neurons in response to NH4Cl. Wortmannin failed to elicit an effect. Shown are the mean and standard error of the mean of at least 3 independent experiments. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 Allocortex vs neocortex; ∧ p ≤ 0.05 or ∧∧∧ p ≤ 0.001 MG132 vs vehicle; +p ≤ 0.05 NH4Cl versus vehicle; Bonferroni post hoc correction following two-way ANOVA. E–F: Infrared Western immunoblotting for ubiquitin-conjugated proteins revealed that Allocortex exhibited higher levels of this measure of proteotoxic stress in response to MG132. G: Proteasome activity was measured in the presence or absence of MG132 in a fluorogenic assay. Allocortical proteasomes were more inhibited by MG132 than those from neocortex. Shown are the mean and standard error of the mean of at least 3 independent experiments. For F and G, *p ≤ 0.05, **p ≤ 0.01 Allocortex versus neocortex;+p ≤ 0.05,+++p ≤ 0.001,++++p ≤ 0.0001 MG132 versus vehicle (0 µM MG132); Bonferroni post hoc correction following two-way ANOVA.
Hailey J. H. Choi - One of the best experts on this subject based on the ideXlab platform.
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Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
2016Co-Authors: Jessica M. Posimo, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:In Parkinson’s and Alzheimer’s diseases, the Allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and Allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in Allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in Allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in Allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as Allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered Allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middl
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Correction: Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
PLoS ONE, 2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:There were multiple errors in the Author Contributions statement. The Author Contributions statement should read: "Conceived and designed the experiments: RKL. Performed the experiments: JMP AMT. Analyzed the data: JMP AMT HJHC ASU. Wrote the paper: RKL."
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Neocortex and Allocortex Respond Differentially to Cellular Stress In Vitro and Aging In Vivo
PloS one, 2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:In Parkinson’s and Alzheimer’s diseases, the Allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and Allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in Allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in Allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in Allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as Allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered Allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middle age. PA28 levels rose with age and were higher in Allocortex in vivo, also paralleling in vitro data. These neo- and allocortical differences have implications for the many studies that treat the telencephalic mantle as a single unit. Our observations suggest that the topographic progression of protein aggregations through the cerebrum may reflect differential responses to low level protein-misfolding stress but also reveal impressive compensatory adaptations in Allocortex.
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Impact of natural aging on neocortex and Allocortex in vivo.
2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:A: Glutathione levels in whole tissue lysates of rat neo- and Allocortex as a function of age. Allocortical glutathione levels were similar to those in neocortex but rose in an age-dependent manner and were significantly higher at 19–22 months of age relative to the youngest group (2–4 months). Neocortical glutathione did not change significantly as a function of age. B–C: Western immunoblotting for ceruloplasmin as a function of age and brain region. Neocortex had much more ceruloplasmin than Allocortex at every age examined. Furthermore, neocortical ceruloplasmin rose in an age-dependent manner until rats were 16–19 months old. D–E: PA28 levels as a function of age in neo- and Allocortex. PA28 levels rose in neocortex at 19–22 months and in Allocortex at 16–19 months relative to the youngest age group. Allocortical PA28 levels were significantly higher than in neocortex at 16–19 months of age. Data are expressed as mean and standard error of the mean from 4–5 rats per group. For all panels, **p ≤ 0.01, ***p ≤ 0.001, Allocortex versus neocortex;+p ≤ 0.05,+++p ≤ 0.001 versus levels in the 2–4 month old group; Bonferroni post hoc correction following two-way ANOVA.
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Involvement of autophagic defenses and ubiquitin-proteasome system.
2013Co-Authors: Jessica M. Posimo, Amanda M. Titler, Hailey J. H. Choi, Ajay S. Unnithan, Rehana K. LeakAbstract:A–B: Infrared Western immunoblotting for macroautophagy-related molecule Beclin 1 following treatment of neo- and allocortical cultures with 0.25 and 1 µM MG132 is shown. β-actin was used as a loading control. C–D: Ammonium chloride (20 mM NH4Cl) was used to inhibit all forms of autophagy and wortmannin (50 nM) was used to inhibit macroautophagy in neo- and allocortical cultures subjected to vehicle or 0.25 µM MG132. Neocortical neurons became as vulnerable to MG132 as allocortical neurons in response to NH4Cl. Wortmannin failed to elicit an effect. Shown are the mean and standard error of the mean of at least 3 independent experiments. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 Allocortex vs neocortex; ∧ p ≤ 0.05 or ∧∧∧ p ≤ 0.001 MG132 vs vehicle; +p ≤ 0.05 NH4Cl versus vehicle; Bonferroni post hoc correction following two-way ANOVA. E–F: Infrared Western immunoblotting for ubiquitin-conjugated proteins revealed that Allocortex exhibited higher levels of this measure of proteotoxic stress in response to MG132. G: Proteasome activity was measured in the presence or absence of MG132 in a fluorogenic assay. Allocortical proteasomes were more inhibited by MG132 than those from neocortex. Shown are the mean and standard error of the mean of at least 3 independent experiments. For F and G, *p ≤ 0.05, **p ≤ 0.01 Allocortex versus neocortex;+p ≤ 0.05,+++p ≤ 0.001,++++p ≤ 0.0001 MG132 versus vehicle (0 µM MG132); Bonferroni post hoc correction following two-way ANOVA.
