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Nat Commun. 2015 May 13;6:7098. doi: 10.1038/ncomms8098.

FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization.

Author information

1
1] Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan [2] Graduate School of pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
2
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
3
Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
4
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
5
Graduate School of pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
6
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
7
Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.

Abstract

FUS is an RNA/DNA-binding protein involved in multiple steps of gene expression and is associated with amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). However, the specific disease-causing and/or modifying mechanism mediated by FUS is largely unknown. Here we evaluate intrinsic roles of FUS on synaptic functions and animal behaviours. We find that FUS depletion downregulates GluA1, a subunit of AMPA receptor. FUS binds GluA1 mRNA in the vicinity of the 3' terminus and controls poly (A) tail maintenance, thus regulating stability. GluA1 reduction upon FUS knockdown reduces miniature EPSC amplitude both in cultured neurons and in vivo. FUS knockdown in hippocampus attenuates dendritic spine maturation and causes behavioural aberrations including hyperactivity, disinhibition and social interaction defects, which are partly ameliorated by GluA1 reintroduction. These results highlight the pivotal role of FUS in regulating GluA1 mRNA stability, post-synaptic function and FTLD-like animal behaviours.

PMID:
25968143
PMCID:
PMC4479014
DOI:
10.1038/ncomms8098
[Indexed for MEDLINE]
Free PMC Article

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