FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis
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Date
2015-04-25
Authors
Kino, Yoshihiro
Washizu, Chika
Kurosawa, Masaru
Yamada, Mizuki
Miyazaki, Haruko
Akagi, Takumi
Hashikawa, Tsutomu
Doi, Hiroshi
Takumi, Toru
Hicks, Geoffrey G
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Abstract
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.
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Citation
Acta Neuropathologica Communications. 2015 Apr 25;3(1):24