Dataset Information

Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions.

ABSTRACT: In Alzheimer's disease (AD) brain, exposure of axons to A? causes pathogenic changes that spread retrogradely by unknown mechanisms, affecting the entire neuron. We found that locally applied A?1-42 initiates axonal synthesis of a defined set of proteins including the transcription factor ATF4. Inhibition of local translation and retrograde transport or knockdown of axonal Atf4 mRNA abolished A?-induced ATF4 transcriptional activity and cell loss. A?1-42 injection into the dentate gyrus (DG) of mice caused loss of forebrain neurons whose axons project to the DG. Protein synthesis and Atf4 mRNA were upregulated in these axons, and coinjection of Atf4 siRNA into the DG reduced the effects of A?1-42 in the forebrain. ATF4 protein and transcripts were found with greater frequency in axons in the brain of AD patients. These results reveal an active role for intra-axonal translation in neurodegeneration and identify ATF4 as a mediator for the spread of AD pathology.

SUBMITTER: Baleriola J

PROVIDER: S-EPMC4149755 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions.

Baleriola Jimena J Walker Chandler A CA Jean Ying Y YY Crary John F JF Troy Carol M CM Nagy Peter L PL Hengst Ulrich U

Cell 20140801 5

In Alzheimer's disease (AD) brain, exposure of axons to Aβ causes pathogenic changes that spread retrogradely by unknown mechanisms, affecting the entire neuron. We found that locally applied Aβ1-42 initiates axonal synthesis of a defined set of proteins including the transcription factor ATF4. Inhibition of local translation and retrograde transport or knockdown of axonal Atf4 mRNA abolished Aβ-induced ATF4 transcriptional activity and cell loss. Aβ1-42 injection into the dentate gyrus (DG) of ...[more]

PMID: 25171414

Similar Datasets

Project description:Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Previous studies reported that chronological age correlates with differential gene expression across different brain regions. However, prior datasets have not disambiguated whether expression associations with age are due to changes in cell numbers and/or gene expression per cell. In this study, we leveraged single nucleus RNA-sequencing (snRNAseq) to examine changes in cell proportions and transcriptomes in four different brain regions, each from 12 donors aged 20-30 years (young) or 60-85 years (old). We sampled 155,192 nuclei from two cortical regions (entorhinal cortex and middle temporal gyrus) and two subcortical regions (putamen and subventricular zone) relevant to neurodegenerative diseases or the proliferative niche. We found no changes in cellular composition of different brain regions with healthy aging. Surprisingly, we did find that each brain region has a distinct aging signature, with only minor overlap in differentially associated genes across regions. Moreover, each cell type shows distinct age-associated expression changes, including loss of protein synthesis genes in cortical inhibitory neurons, axonogenesis genes in excitatory neurons and oligodendrocyte precursor cells, enhanced gliosis markers in astrocytes and disease-associated markers in microglia, and genes critical for neuron-glia communication. Importantly, we find cell type-specific enrichments of age associations with genes nominated by Alzheimer's disease and Parkinson's disease genome-wide association studies (GWAS), such as apolipoprotein E (APOE), and leucine-rich repeat kinase 2 (LRRK2) in microglia that are independent of overall expression levels across cell types. We present this data as a new resource which highlights, first, region- and cell type-specific transcriptomic changes in healthy aging that may contribute to selective vulnerability and, second, provide context for testing GWAS-nominated disease risk genes in relevant subtypes and developing more targeted therapeutic strategies. The data is readily accessible without requirement for extensive computational support in a public website, https://brainexp-hykyffa56a-uc.a.run.app/.

Dataset Information

Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions.

Publications

Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets