Abstract
Genetic mutations in FUS, a DNA/RNA‐binding protein, are associated with inherited forms of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A novel transgenic FUS[1‐359]‐tg mouse line recapitulates core hallmarks of human ALS in the spinal cord, including neuroinflammation and neurodegeneration, ensuing muscle atrophy and paralysis, as well as brain pathomorphological signs of FTLD. However, a question whether FUS[1‐359]‐tg mouse displays behavioural and brain pro‐inflammatory changes characteristic for the FTLD syndrome was not addressed. Here, we studied emotional, social and cognitive behaviours, brain markers of inflammation and plasticity of pre‐symptomatic FUS[1‐359]‐tg male mice, a potential FTLD model. These animals displayed aberrant behaviours and altered brain expression of inflammatory markers and related pathways that are reminiscent to the FTLD‐like syndrome. FTLD‐related behavioural and molecular Journal of Cellular and Molecular Medicine features were studied in the pre‐symptomatic FUS[1‐359]‐tg mice that received standard or new ALS treatments, which have been reported to counteract the ALS‐like syndrome in the mutants. We used anti‐ALS drug riluzole (8 mg/kg/d), or anti‐inflammatory drug, a selective blocker of cyclooxygenase‐2 (celecoxib, 30 mg/kg/d) for 3 weeks, or a single intracerebroventricular (i.c.v.) infusion of human stem cells (Neuro‐Cells, 500 000‐CD34+), which showed anti‐inflammatory properties. Signs of elevated anxiety, depressive‐like behaviour, cognitive deficits and abnormal social behaviour were less marked in FUS‐tg–treated animals. Applied treatments have normalized protein expression of interleukin‐1β (IL‐1β) in the prefrontal cortex and the hippocampus, and of Iba‐1 and GSK‐3β in the hippocampus. Thus, the pre‐symptomatic FUS[1‐359]‐tg mice demonstrate FTLD‐like abnormalities that are attenuated by standard and new ALS treatments, including Neuro‐Cell preparation.
Highlights
Genetic mutations in FUS, which is DNA/RNA-binding protein, can cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS).1 FTLD is a debilitating disease, often accompanying ALS and involving atrophy of the frontal/temporal lobes and affecting emotional, social and cognitive functions.2 Until recently, the contribution of FUS to the FTLD/ALS pathology remains poorly understood
The available FTLD models based on the FUS mutation often report somewhat non-specific behavioural deficits and limited brain pathology with a late onset,3 or the very rapid development of physiological and motor ALS-like pathology4, and, for this reason, it has been argued that further refinement is required
Hitherto the FTDL-like behavioural features and the accompanying molecular changes have not been investigated. Were addressed this outstanding issue by studying the impact of therapy used in the clinic and new anti-inflammatory therapies on emotional, cognitive and social abnormalities in FUS-tg animals. These therapies have been shown to reduce the ALS-like pathology in these mutants
Summary
Genetic mutations in FUS, which is DNA/RNA-binding protein, can cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). FTLD is a debilitating disease, often accompanying ALS and involving atrophy of the frontal/temporal lobes and affecting emotional, social and cognitive functions. Until recently, the contribution of FUS to the FTLD/ALS pathology remains poorly understood. The construction of the FUS[1-359]-tg mice, expressing truncated human FUS[1-359], has been shown to exhibit many of the hallmark characteristics of ALS, and FTDL-like changes during the pre-symptomatic stage.7 This model provides a promising tool to explore the temporal contribution of FUS mutations on molecular and behavioural outcome. Hitherto the FTDL-like behavioural features and the accompanying molecular changes have not been investigated Were addressed this outstanding issue by studying the impact of therapy used in the clinic and new anti-inflammatory therapies on emotional, cognitive and social abnormalities in FUS-tg animals. These therapies have been shown to reduce the ALS-like pathology in these mutants.
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