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

Abstract

IntroductionFUS/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.ResultsHere, 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.ConclusionsCollectively, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0202-6) contains supplementary material, which is available to authorized users.

Physiological functions and pathobiology of TDP‐43 and FUS/TLS proteins

“…; Kino et al . ). For certain, mutations in both TDP‐43 and FUS seem to work mostly in a gain‐of‐function manner (but probably not exclusively).…”

“…The extent to which all the described biological functions mediated by TDP-43 and FUS contribute to disease is still not very clear. Most of the cellular and animal models made using wild-type and mutant forms of these proteins have not been able to provide a consensus and readers are referred to several reviews and studies appearing recently on this specific issue (Wegorzewska and Baloh 2011;Xu 2012;Armstrong and Drapeau 2013;Vanden Broeck et al 2014;Kino et al 2015). For certain, mutations in both TDP-43 and FUS seem to work mostly in a gain-of-function manner (but probably not exclusively).…”

Role of FET proteins in neurodegenerative disorders

“…Although Fus/Tls −/− mice do not manifest ALS- or ET-like phenotypes until nearly 2 years, they show distinct histological and behavioral alterations upon aging, including vacuolation in hippocampus, hyperactivity, and reduction in anxiety-like behavior 37 . Knockout mice show changes in the expression of genes related to neurological diseases, including upregulation of Taf15 and Hnrnpa1 , while they have normal morphology of RNA-related granules 37 .…”

Roles for RNA-binding proteins in development and disease

“…Homozygous knockout of Fus produces perinatal lethality in inbred mouse lines (Hicks et al, 2000). However, Fus knockout animals survived in an outbred strain, but developed neurodegenerative pathology (Kino et al, 2015). During postnatal development, FUS protein levels decrease in brain, skeletal muscle, heart, and liver tissue while mRNA levels remain constant (Huang et al, 2010).…”

“…Mutated FUS seen in ALS patients causes a loss of interaction between FUS and U1 snRNP (Sun et al, 2015) suggesting the potential for pathogenic effects via disrupted co-transcriptional RNA processing. Although FUS loss does not cause lethality, it causes a unique neurodegenerative phenotype distinctive from ALS, which indicates that FUS loss-of-function is disruptive to normal neural function but may not be the driving force of ALS pathogenesis (Kino et al, 2015). FUS gains function through mutations that have a greater association with SMN protein in the cytoplasm (Sun et al, 2015).…”