A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice

Abstract

Aims To assess effects of DF402, a bioisostere of Dimebon/Latrepirdine, on the disease progression in the transgenic model of amyotrophic lateral sclerosis (ALS) caused by expression of pathogenic truncated form of human FUS protein. Methods Mice received DF402 from the age of 42 days and the onset of clinical signs, the disease duration and animal lifespan were monitored for experimental and control animals, and multiple parameters of their gait were assessed throughout the pre‐symptomatic stage using CatWalk system followed by a bioinformatic analysis. RNA‐seq was used to compare the spinal cord transcriptomes of wild‐type, untreated, and DF402‐treated FUS transgenic mice. Results DF402 delays the onset and slows the progression of pathology. We developed a CatWalk analysis protocol that allows detection of gait changes in FUS transgenic mice and the effect of DF402 on their gait already at early pre‐symptomatic stage. At this stage, a limited number of genes significantly change expression in transgenic mice and for 60% of these genes, DF402 treatment causes the reversion of the expression pattern. Conclusion DF402 slows down the disease progression in the mouse model of ALS, which is consistent with previously reported neuroprotective properties of Dimebon and its other bioisosteres. These results suggest that these structures can be considered as lead compounds for further optimization to obtain novel medicines that might be used as components of complex ALS therapy.

Lipopolysaccharide triggers exacerbated microglial activation, excessive cytokine release and behavioural disturbances in mice with truncated Fused-in-Sarcoma Protein (FUS)

“…Our study has revealed the presence of an increased sensitivity of microglia to inflammatory challenges at in early pre-symptomatic stages of the ALS/FTLD-like syndrome in mice with compromised FUS function. It is accompanied by elevated CNS cytokine production under unchallenged conditions and is present prior any signs of neurodegeneration in FUS-tg mutants ( de Munter et al, 2020b ; Chaprov et al, 2021 ), thus suggesting these pro-inflammatory processes are independent of neuronal cell death. Finally, the FUS[1–359]-tg mouse line used here can be a useful model to address the role of microglia and inflammation in the mechanisms of ALS/FTLD syndrome further.…”

“…Earlier studies with the FUS[1–359]-tg mice revealed that the pathology is associated with over-expression of the pro-inflammatory cytokines IL-1β and IL-6 in the brain, blood and spinal cord, and behavioural deficits in the symptomatic FUS[1–359]-tg mice ( de Munter et al, 2020a , 2020b ; Probert et al, 2022 ; Lysikova et al, 2019 ). However, gene expression studies failed to reveal any signs of altered microglial function or of inflammatory markers in the CNS of naïve pre-symptomatic FUS[1–359]-tg mice ( Chaprov et al, 2021 ). Here, we studied immunohistochemical expression of Iba-1 in the prefrontal cortex (PFC), hippocampus (HIP) and spinal cord (SC) of naïve pre-symptomatic 8-week old FUS[1–359]-tg mice 24 h after an LPS injection.…”

Increasing brain N‐acetylneuraminic acid alleviates hydrocephalus‐induced neurological deficits

“…The rotarod test, foot‐fault test, CatWalk gait analysis, novel object recognition test, and open‐field test were performed according to a previously described protocols. 43 , 44 , 45 , 46 The balance ability of mice was assessed using a rotarod apparatus (Ugo Basile). The average latency time of three trials to fall off the rotating rod was recorded.…”

Behavioral Paradigms in Rodent Models of Amyotrophic Lateral Sclerosis

“…Additionally, motor deficits have been successfully identified through gait analysis in other ALS mouse models, demonstrating the versatility of this approach in studying the disease. For example, gait analysis has been applied to transgenic mouse models induced by the expression of pathogenic truncated forms of the human FUS (fused in sarcoma) gene 34 or by transgenic mice expressing full-length hTDP-43 under the control of the mouse prion promoter. 32 These findings further highlight the utility of gait analysis as a valuable tool for characterizing motor defects in various ALS models, contributing to our understanding of the disease and potential therapeutic interventions.…”