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

• Published in: Acta neuropathologica communications Vol. 3; no. 1; p. 24
• Main Authors: Kino, Yoshihiro, Washizu, Chika, Kurosawa, Masaru, Yamada, Mizuki, Miyazaki, Haruko, Akagi, Takumi, Hashikawa, Tsutomu, Doi, Hiroshi, Takumi, Toru, Hicks, Geoffrey G, Hattori, Nobutaka, Shimogori, Tomomi, Nukina, Nobuyuki
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 25-04-2015; BioMed Central
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Anxiety - psychology; Behavior, Animal; Brain; Development and progression; Disease Models, Animal; Essential Tremor - genetics; Essential Tremor - physiopathology; Gene mutations; Genetic aspects; Health aspects; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - genetics; Homozygote; Hyperkinesis; Mice; Mice, Inbred C57BL; Mice, Knockout; Nervous system diseases; Neurophysiology; Phenotype; Physiological aspects; Protein binding; RNA; RNA-Binding Protein FUS - deficiency; RNA-Binding Protein FUS - genetics; RNA-Binding Proteins - genetics; TATA-Binding Protein Associated Factors - genetics; Tremor; Up-Regulation
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-015-0202-6

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.
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.
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.