Activity-Dependent FUS Dysregulation Disrupts Synaptic Homeostasis

DSpace/Manakin Repository

Activity-Dependent FUS Dysregulation Disrupts Synaptic Homeostasis

Show full item record

Title: Activity-Dependent FUS Dysregulation Disrupts Synaptic Homeostasis
Author(s):
Sephton, Chantelle F.;
Tang, Amy A.;
Kulkarni, Ashwinikumar;
West, James;
Brooks, Mieu;
Stubblefield, Jeremy J.;
Liu, Yun;
Zhang, Michael Q.;
Green, Carla B.;
Huber, Kimberly M.;
Huang, Eric J.;
Herz, Joachim;
Yu, Gang
Item Type: Article
Keywords: Show Keywords
Description: This article contains supporting information online at: http://www.pnas.org/content/111/44/E4769/suppl/DCSupplemental
Abstract: The RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUSWT) and a pathological mutation (FUSR521G). FUSWT and FUSR521G mice that develop severe motor deficits also show neuroinflammation, denervated neuromuscular junctions, and premature death, phenocopying the human diseases. A portion of FUSR521G mice escape early lethality; these escapers have modest motor impairments and altered sociability, which correspond with a reduction of dendritic arbors and mature spines. Remarkably, only FUSR521G mice show dendritic defects; FUSWT mice do not. Activation of metabotropic glutamate receptors 1/5 in neocortical slices and isolated synaptoneurosomes increases endogenous mouse FUS and FUSWT protein levels but decreases the FUSR521G protein, providing a potential biochemical basis for the dendritic spine differences between FUSWT and FUSR521G mice.
Publisher: Natl Acad Sciences
ISSN: 0027-8424
Persistent Link: http://hdl.handle.net/10735.1/4236
http://dx.doi.org/10.1073/pnas.1406162111
Terms of Use: ©2014 The Authors. "Freely available online through the PNAS open access option."

Files in this item

Files Size Format View

There are no files associated with this item.

This item appears in the following Collection(s)


Show full item record