Transgenic mice with decreased level of the pathogenic form of human FUS protein display cognitive impairment

Abstract

Background. Pathological aggregation of the DNA/RNA-binding FUS protein is associated with development of amyotrophic lateral sclerosis (ALS) and frontal-temporal lobar degeneration (FTLD). The original strain of transgenic mice, FUS[1-359] with neurospecific expression of the truncated form of human FUS protein is characterized by progressive neurodegeneration of motor neurons and early lethality, which matches the ALS phenotype. After four generations of backcrossing, a substrain of L_FUS [1-359] mice was isolated, which had increased lifespan and no phenotypic motor disorders.
Aim. The aim of the study was to characterize the L_FUS[1-359] substrain as a FTLD model.
Materials and methods. The number of copies and expression levels of the transgenic cassette were compared in the original strain and the transgenic substrain using quantitative RT-PCR. Cognitive function of animals was evaluated using a battery of behavioral tests.
Results. Animals of the original strain and the transgenic substrain had an equal number of copies of the same transgenic cassette but the level of human FUS expression was 10 times lower in the nervous system of L_FUS[1-359] mice than in the original strain. Results of behavioral tests for the cognitive function showed that L_FUS [1-359] mice developed statistically significant deviations by the age of 7 months, which indicated a change in the emotional condition.
Conclusion. The results of the study suggested that L_FUS [1-359] mice may represent a model of slowly progressing FUSproteinopathy with the FTLD phenotype.