Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment.
Disturbed proteostasis as a particular phenotype of the aging organism has been advanced in C. elegans experiments and is also conceived to underlie neurodegenerative diseases in humans. Here, we investigated whether particular changes in non-disease related proteostasis can be identified in the age...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3777897?pdf=render |
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| author | Philipp Ottis Bianca Topic Maarten Loos Ka Wan Li Angelica de Souza Daniela Schulz August B Smit Joseph P Huston Carsten Korth |
| author_facet | Philipp Ottis Bianca Topic Maarten Loos Ka Wan Li Angelica de Souza Daniela Schulz August B Smit Joseph P Huston Carsten Korth |
| author_sort | Philipp Ottis |
| collection | DOAJ |
| description | Disturbed proteostasis as a particular phenotype of the aging organism has been advanced in C. elegans experiments and is also conceived to underlie neurodegenerative diseases in humans. Here, we investigated whether particular changes in non-disease related proteostasis can be identified in the aged mammalian brain, and whether a particular signature of aberrant proteostasis is related to behavioral performance of learning and memory. Young (adult, n = 30) and aged (2 years, n = 50) Wistar rats were tested in the Morris Water Maze (MWM) to distinguish superior and inferior performers. For both young and old rats, the best and worst performers in the MWM were selected and the insoluble proteome, termed aggregome, was purified from the hippocampus as evidence for aberrant proteostasis. Quantitative proteomics (iTRAQ) was performed. The aged inferior performers were considered as a model for spontaneous, age-associated cognitive impairment. Whereas variability of the insoluble proteome increased with age, absolute changes in the levels of insoluble proteins were small compared to the findings in the whole C. elegans insoluble proteome. However, we identified proteins with aberrant proteostasis in aging. For the cognitively impaired rats, we identified a changed molecular circuitry of proteins selectively involved in F-actin remodeling, synapse building and long-term depression: actin related protein 3 (ARP3), neurabin II (NEB2) and IQ motif and SEC7 domain-containing protein 1 (BRAG2). We demonstrate that aberrant proteostasis is a specific phenotype of brain aging in mammals. We identify a distinct molecular circuitry where changes in proteostasis are characteristic for poor learning and memory performance in the wild type, aged rat. Our findings 1. establish the search for aberrant proteostasis as a successful strategy to identify neuronal dysfunction in deficient cognitive behavior, 2. reveal a previously unknown functional network of proteins (ARP3, NEB2, BRAG2) involved in age-associated cognitive dysfunction. |
| first_indexed | 2024-12-10T08:14:53Z |
| format | Article |
| id | doaj.art-74c37a9513594bcfa9de8b36bd1b78e6 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T08:14:53Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-74c37a9513594bcfa9de8b36bd1b78e62022-12-22T01:56:29ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0189e7511210.1371/journal.pone.0075112Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment.Philipp OttisBianca TopicMaarten LoosKa Wan LiAngelica de SouzaDaniela SchulzAugust B SmitJoseph P HustonCarsten KorthDisturbed proteostasis as a particular phenotype of the aging organism has been advanced in C. elegans experiments and is also conceived to underlie neurodegenerative diseases in humans. Here, we investigated whether particular changes in non-disease related proteostasis can be identified in the aged mammalian brain, and whether a particular signature of aberrant proteostasis is related to behavioral performance of learning and memory. Young (adult, n = 30) and aged (2 years, n = 50) Wistar rats were tested in the Morris Water Maze (MWM) to distinguish superior and inferior performers. For both young and old rats, the best and worst performers in the MWM were selected and the insoluble proteome, termed aggregome, was purified from the hippocampus as evidence for aberrant proteostasis. Quantitative proteomics (iTRAQ) was performed. The aged inferior performers were considered as a model for spontaneous, age-associated cognitive impairment. Whereas variability of the insoluble proteome increased with age, absolute changes in the levels of insoluble proteins were small compared to the findings in the whole C. elegans insoluble proteome. However, we identified proteins with aberrant proteostasis in aging. For the cognitively impaired rats, we identified a changed molecular circuitry of proteins selectively involved in F-actin remodeling, synapse building and long-term depression: actin related protein 3 (ARP3), neurabin II (NEB2) and IQ motif and SEC7 domain-containing protein 1 (BRAG2). We demonstrate that aberrant proteostasis is a specific phenotype of brain aging in mammals. We identify a distinct molecular circuitry where changes in proteostasis are characteristic for poor learning and memory performance in the wild type, aged rat. Our findings 1. establish the search for aberrant proteostasis as a successful strategy to identify neuronal dysfunction in deficient cognitive behavior, 2. reveal a previously unknown functional network of proteins (ARP3, NEB2, BRAG2) involved in age-associated cognitive dysfunction.http://europepmc.org/articles/PMC3777897?pdf=render |
| spellingShingle | Philipp Ottis Bianca Topic Maarten Loos Ka Wan Li Angelica de Souza Daniela Schulz August B Smit Joseph P Huston Carsten Korth Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment. PLoS ONE |
| title | Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment. |
| title_full | Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment. |
| title_fullStr | Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment. |
| title_full_unstemmed | Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment. |
| title_short | Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment. |
| title_sort | aging induced proteostatic changes in the rat hippocampus identify arp3 neb2 and brag2 as a molecular circuitry for cognitive impairment |
| url | http://europepmc.org/articles/PMC3777897?pdf=render |
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