Format

Send to

Choose Destination
Acta Neuropathol Commun. 2015 Apr 25;3:24. doi: 10.1186/s40478-015-0202-6.

FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis.

Kino Y1,2,3,4,5, Washizu C6, Kurosawa M7,8,9,10, Yamada M11, Miyazaki H12,13,14,15, Akagi T16, Hashikawa T17, Doi H18, Takumi T19,20,21, Hicks GG22, Hattori N23, Shimogori T24, Nukina N25,26,27,28.

Author information

1
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan. kino@my-pharm.ac.jp.
2
CREST (Core Research for Evolutionary Science and Technology), JST, Saitama, Japan. kino@my-pharm.ac.jp.
3
Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. kino@my-pharm.ac.jp.
4
Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan. kino@my-pharm.ac.jp.
5
Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan. kino@my-pharm.ac.jp.
6
Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. c_washizu@brain.riken.jp.
7
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan. kurosawa@brain.riken.jp.
8
CREST (Core Research for Evolutionary Science and Technology), JST, Saitama, Japan. kurosawa@brain.riken.jp.
9
Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. kurosawa@brain.riken.jp.
10
Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan. kurosawa@brain.riken.jp.
11
Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. y-mizuki@brain.riken.jp.
12
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan. miyazaki@brain.riken.jp.
13
CREST (Core Research for Evolutionary Science and Technology), JST, Saitama, Japan. miyazaki@brain.riken.jp.
14
Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. miyazaki@brain.riken.jp.
15
Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan. miyazaki@brain.riken.jp.
16
Research Resource Center, Brain Science Institute, RIKEN, Saitama, Japan. atakumi@brain.riken.jp.
17
Research Resource Center, Brain Science Institute, RIKEN, Saitama, Japan. tom@brain.riken.jp.
18
Department of Clinical Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Japan. doi@rkd.d-bs.com.
19
CREST (Core Research for Evolutionary Science and Technology), JST, Saitama, Japan. toru.takumi@riken.jp.
20
Laboratory for Mental Biology, Brain Science Institute, RIKEN, Saitama, Japan. toru.takumi@riken.jp.
21
Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. toru.takumi@riken.jp.
22
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada. hicksgg@cc.umanitoba.ca.
23
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan. nhattori@juntendo.ac.jp.
24
Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan. tshimogori@brain.riken.jp.
25
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan. nnukina@juntendo.ac.jp.
26
CREST (Core Research for Evolutionary Science and Technology), JST, Saitama, Japan. nnukina@juntendo.ac.jp.
27
Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama, Japan. nnukina@juntendo.ac.jp.
28
Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan. nnukina@juntendo.ac.jp.

Abstract

INTRODUCTION:

FUS/TLS is an RNA-binding protein whose genetic mutations or pathological inclusions are associated with neurological diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and essential tremor (ET). It is unclear whether their pathogenesis is mediated by gain or loss of function of FUS/TLS.

RESULTS:

Here, we established outbred FUS/TLS knockout mice to clarify the effects of FUS/TLS dysfunction in vivo. We obtained homozygous knockout mice that grew into adulthood. Importantly, they did not manifest ALS- or ET-like phenotypes until nearly two years. Instead, they showed distinct histological and behavioral alterations including vacuolation in hippocampus, hyperactivity, and reduction in anxiety-like behavior. Knockout mice showed transcriptome alterations including upregulation of Taf15 and Hnrnpa1, while they have normal morphology of RNA-related granules such as Gems.

CONCLUSIONS:

Collectively, FUS/TLS depletion causes phenotypes possibly related to neuropsychiatric and neurodegenerative conditions, but distinct from ALS and ET, together with specific alterations in RNA metabolisms.

PMID:
25907258
PMCID:
PMC4408580
DOI:
10.1186/s40478-015-0202-6
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center