TY - JOUR
T1 - FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis
AU - Kino, Yoshihiro
AU - Washizu, Chika
AU - Kurosawa, Masaru
AU - Yamada, Mizuki
AU - Miyazaki, Haruko
AU - Akagi, Takumi
AU - Hashikawa, Tsutomu
AU - Doi, Hiroshi
AU - Takumi, Toru
AU - Hicks, Geoffrey G.
AU - Hattori, Nobutaka
AU - Shimogori, Tomomi
AU - Nukina, Nobuyuki
N1 - Funding Information:
We would like to thank Ms. Itsuko Yamamoto and Ms. Tomoko Yoda for animal maintenance, Dr. Kazuyuki Yamada for advices, the Research Resource Center staff of RIKEN Brain Science Institute for DNA sequencing and microarray processing. This work was supported by Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology to Y.K. (23791007 and 25461299) and to N.N. (22110004, 22240037, 24659436, 25253066), by CREST from JST for N.N., and by Grant-in-Aid for the Research on Measures for Ataxic Diseases from the Ministry of Health, Welfare and Labor to N.N.
PY - 2015/4/25
Y1 - 2015/4/25
N2 - 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.
AB - 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.
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U2 - 10.1186/s40478-015-0202-6
DO - 10.1186/s40478-015-0202-6
M3 - Article
C2 - 25907258
AN - SCOPUS:85018214664
SN - 2051-5960
VL - 3
SP - 24
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
ER -