RGD Reference Report - Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment. - Rat Genome Database

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Aging-induced proteostatic changes in the rat hippocampus identify ARP3, NEB2 and BRAG2 as a molecular circuitry for cognitive impairment.

Authors: Ottis, P  Topic, B  Loos, M  Li, KW  De Souza, A  Schulz, D  Smit, AB  Huston, JP  Korth, C 
Citation: Ottis P, etal., PLoS One. 2013 Sep 19;8(9):e75112. doi: 10.1371/journal.pone.0075112. eCollection 2013.
RGD ID: 9999367
Pubmed: PMID:24069387   (View Abstract at PubMed)
PMCID: PMC3777897   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0075112   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Cognitive Dysfunction  ISOActr3 (Rattus norvegicus)9999367; 9999367protein:altered localization:hippocampus (rat)RGD 
Cognitive Dysfunction  IEP 9999367protein:altered localization:hippocampus (rat)RGD 
Cognitive Dysfunction  ISOPpp1r9b (Rattus norvegicus)9999367; 9999367protein:decreased expression:hippocampus and insoluble fraction (rat)RGD 
Cognitive Dysfunction  IEP 9999367protein:decreased expression:hippocampus and insoluble fraction (rat)RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
learning  IEP 9999367; 9999367 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Actr3  (actin related protein 3)
Ppp1r9b  (protein phosphatase 1, regulatory subunit 9B)
Ptn  (pleiotrophin)

Genes (Mus musculus)
Actr3  (ARP3 actin-related protein 3)
Ppp1r9b  (protein phosphatase 1, regulatory subunit 9B)

Genes (Homo sapiens)
ACTR3  (actin related protein 3)
PPP1R9B  (protein phosphatase 1 regulatory subunit 9B)


Additional Information