Abstract
AimsTo 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.MethodsMice 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.ResultsDF402 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.ConclusionDF402 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.
Highlights
Gamma-carbolines have attracted attention as potential neuroprotectors in the nervous system affected by neurodegenerative processes.5–14 Their neuroprotective activity can be explained by a combination of multiple mechanisms of action described for these compounds.11,15–28 Irreversible pathological aggregation of certain proteins contributes to pathogenesis of all types of amyotrophic lateral sclerosis (ALS) and it is an obvious target for therapeutic intervention
We show that a large fraction of DEG observed in the comparison of S-FUS[1–359] and wild-type samples have undergone the compensation in their expression levels, indicating that DF-402 treatment substantially ameliorates the gene expression changes induced by FUS transgene expression in the spinal cord neurons (Figure 4B, Figure S3)
By comparing data obtained in longitudinal studies of the CatWalk performance of control and DF402-treated S-FUS[1–359] mice, we demonstrated that a multifactorial analysis of gait parameters used in this study is sufficiently robust to detect and monitor even mild effects of drugs or other therapeutic interventions from the early stage of motor neuron disease in this transgenic model
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily characterized by dysfunction and death of lower and upper motor neurons. An ability of Dimebon to prevent accumulation of cytoplasmic proteinaceous inclusions has been first demonstrated in cultured neurons expressing a highly aggregation-prone variant of RNA-binding protein TDP-43.29 Further studies in various cellular models of proteinopathies confirmed anti-aggregation properties of Dimebon and demonstrated its ability to activate autophagic mechanism of pathological aggregate elimination.[10,11,21,22,27,30] Consistently, chronic treatment with Dimebon, when started at a pre-symptomatic stage of the disease, delayed the onset of clinical signs, slowed down disease progression, and increased animal lifespan in several mouse models of neurodegeneration, including those that recapitulate key features of ALS.[7,9,28,31,32] the efficacy of Dimebon in ameliorating pathology in these models was low and in attempt to produce more efficient compounds, several bioisosteres of Dimebon have been synthesized. Data sets for the disease onset, disease duration, animal lifespan, and RT-qPCR analysis of RNA expression were assessed for normal distribution and for those that passed D'Agostino and Pearson test, statistical significance of observed difference was evaluated by one- way ANOVA or paired t-test, as appropriate. For not normally distributed data, Kruskal-Wallis ANOVA and/or Mann-Whitney U-test were used
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