Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.

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 the...

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Autores principales:	Jessica M Posimo, Amanda M Titler, Hailey J H Choi, Ajay S Unnithan, Rehana K Leak
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/69f333461b6541ccb32273d44f209d8a
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spelling	oai:doaj.org-article:69f333461b6541ccb32273d44f209d8a2021-11-18T07:53:58ZNeocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.1932-620310.1371/journal.pone.0058596https://doaj.org/article/69f333461b6541ccb32273d44f209d8a2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23536801/?tool=EBIhttps://doaj.org/toc/1932-6203In 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.Jessica M PosimoAmanda M TitlerHailey J H ChoiAjay S UnnithanRehana K LeakPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 3, p e58596 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jessica M Posimo Amanda M Titler Hailey J H Choi Ajay S Unnithan Rehana K Leak Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.
description	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.
format	article
author	Jessica M Posimo Amanda M Titler Hailey J H Choi Ajay S Unnithan Rehana K Leak
author_facet	Jessica M Posimo Amanda M Titler Hailey J H Choi Ajay S Unnithan Rehana K Leak
author_sort	Jessica M Posimo
title	Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.
title_short	Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.
title_full	Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.
title_fullStr	Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.
title_full_unstemmed	Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.
title_sort	neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/69f333461b6541ccb32273d44f209d8a
work_keys_str_mv	AT jessicamposimo neocortexandallocortexresponddifferentiallytocellularstressinvitroandaginginvivo AT amandamtitler neocortexandallocortexresponddifferentiallytocellularstressinvitroandaginginvivo AT haileyjhchoi neocortexandallocortexresponddifferentiallytocellularstressinvitroandaginginvivo AT ajaysunnithan neocortexandallocortexresponddifferentiallytocellularstressinvitroandaginginvivo AT rehanakleak neocortexandallocortexresponddifferentiallytocellularstressinvitroandaginginvivo
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Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.

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