Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling.

Authors: Berson, Amit; Sartoris, Ashley; Nativio, Raffaella; Van Deerlin, Vivianna; Toledo, Jon B; Porta, Sílvia; Liu, Shichong; Chung, Chia-Yu; Garcia, Benjamin A; Lee, Virginia M-Y; Trojanowski, John Q; Johnson, F Brad; Berger, Shelley L; Bonini, Nancy M

Published In Curr Biol, (2017 Dec 04)

Abstract: Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43-mediated impairments are conserved in mammalian cells, and, importantly, the human ortholog CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to amyotrophic lateral scleorosis (ALS)/frontotemporal dementia (FTD).

PubMed ID: 29153328 Exiting the NIEHS site

MeSH Terms: Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis/genetics*; Amyotrophic Lateral Sclerosis/metabolism; Amyotrophic Lateral Sclerosis/physiopathology; Animals; Chromatin Assembly and Disassembly*; DNA-Binding Proteins/genetics*; DNA-Binding Proteins/metabolism; Disease Models, Animal; Drosophila Proteins/genetics*; Drosophila Proteins/metabolism; Drosophila melanogaster/genetics*; Drosophila melanogaster/metabolism; Frontotemporal Dementia/genetics*; Frontotemporal Dementia/metabolism; Frontotemporal Dementia/physiopathology; HEK293 Cells; Heat-Shock Proteins/metabolism; Humans; Male; Middle Aged

Back
to Top