Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

Abstract

Multiple clinical and experimental evidences suggest that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are members of a disease continuum. Pathological inclusions of fused in sarcoma (FUS) protein have been observed in subsets of patients with these diseases but their anatomical distribution is different for two diseases. These structures are present in motor neurons in ALS cases but in cortical neurons in FTLD cases. Expression of a C‐terminally truncated form of human FUS causes an early onset and progressive motor neuron pathology in transgenic mice but only when these neurons express a certain level of this protein. Severe motor dysfunction and early lethality of mice with expression above this level prevent their use for studies of FTLD‐related pathology caused by expression of this form of FUS. In the present study, we used another line of mice expressing the same protein but not developing any signs of motor system dysfunction due to substantially lower level of transgene expression in motor neurons. In a set of tests 5‐month old mice displayed certain behavioural abnormalities, including increased impulsivity, decreased anxiety and compromised social interaction, which recapitulate behaviour characteristics typically seen in FTLD patients.

Molecular and behavioural abnormalities in the FUS‐tg mice mimic frontotemporal lobar degeneration: Effects of old and new anti‐inflammatory therapies

“…The current study suggests the most prominent FDTL‐related deficits of the FUS‐tg mice are the classic tests of emotionality, social and hippocampus‐dependent performance. In comparison with other FTLD rodent models based on the FUS mutation, the findings reported here in the FUS‐tg mice suggest that no hyperactivity or other non‐specific behavioural alternations are present, but, typical for this disease, features of anxiety, apathy, cognitive and social deficits are observed 3,5,7 . Hippocampal concentrations of TNF and COX‐1 mRNA were elevated in the FUS‐tg mice ( P < .05 vs controls; unpaired t test; Figure 1H‐M, Table ).…”

“…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 pathology 4 , and, for this reason, it has been argued that further refinement is required 5 . 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, 6 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.…”

Neuro‐Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice

“…Therefore, we have employed a FUS[1‐359]‐tg mouse model according to the guidelines set by Ludolph et al, 2010, for ALS preclinical studies that have recommended the use of other ALS models apart from the SOD‐1 mouse “gold standard” . The pattern of pathology in FUS[1‐359]‐tg line recapitulates key features of human ALS, including motor neuron degeneration and microgliosis in the brainstem and spinal cord, muscle atrophy, paralysis, microglial activation, and elevated levels of pro‐inflammatory cytokines in the CNS and blood . The model permits the impact of therapy on ALS‐related changes to be evaluated including basic physiological and motor functions, as well as evaluation of the expression of pro‐inflammatory and degeneration markers such as Iba‐1, GSK‐3ß, IL‐1ß, and IL‐6 in the lumbar spinal cord and blood levels of IL‐1ß and IL‐6.…”

The patient's own bone marrow-derived stromal cells

“…Therefore, we have employed a FUS[1-359]-tg mouse model (Shelkovnikova, Peters et al 2013) according to the guidelines set by Ludolph et al, 2010, for ALS preclinical studies (Ludolph, Bendotti et al 2010) that have recommended the use of other ALS models apart from the SOD-1 mouse "gold standard" (Gurney, Pu et al 1994). The pattern of pathology in FUS[1-359]-tg line recapitulates key features of human ALS, including motor neuron degeneration and microgliosis in the brainstem and spinal cord, muscle atrophy, paralysis, microglial activation, and elevated levels of pro-inflammatory cytokines in the CNS and blood (Shelkovnikova, Peters et al 2013, Lysikova, Kukharsky et al 2019). The model permits the impact of therapy on ALS-related changes to be evaluated including basic physiological and motor functions, as well as evaluation of the expression of pro-inflammatory and degeneration markers such as Iba-1, GSK-3ß, IL-1ß, and IL-6 in the lumbar spinal cord and blood levels of IL-1ß and IL-6.…”

“…The available FTLD models based on the FUS mutation often report somewhat non-specific behavioural deficits and limited brain pathology with a late onset (Shiihashi, Ito et al 2017), or the very rapid development of physiological and motor ALS-like pathology (Kasey, Hemangini et al 2016), and, for this reason, it has been argued that further refinement is required (Nolan, Talbot et al 2016). 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 (Shelkovnikova, Peters et al 2013), and FTDL-like changes during the pre-symptomatic stage (Lysikova, Kukharsky et al 2019). This model provides a promising tool to explore the temporal contribution of FUS mutations on molecular and behavioural outcome.…”