GSE161680
A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice
Despite intensive studies that improved our understanding of the disease mechanisms and multiple clinical trials, amyotrophic lateral sclerosis (ALS) remains an uncurable disease. Riluzole and Edaravone, two currently approved drugs, provide limited quality-of-life improvements in ALS patients. This emphasises the importance of searching for new drugs and therapeutic approaches that might be used, most probably in combination, for efficient treatment of ALS. A neuroprotective ability of certain gamma-carbolines, including Dimebon/Latrepirdine and its derivates, has been demonstrated in several models of neurodegeneration, suggesting that these compounds have a potential as components of a multiplex disease-modifying therapy of ALS. In this study we showed that a chronic treatment with a novel Dimebon bioisostere, DF402, delays the onset and slows the progression of pathology in the transgenic model of motor neuron disease caused by expression of pathogenic truncated form of human FUS protein. By using CatWalk gait analysis we have revealed parameters of transgenic animal gait that display changes before manifestation of clinical signs of pathology and parameters that are changed at the pre-symptomatic stage in response to DF402 treatment. RNAseq was used to compare the spinal cord transcriptomes of wild type, untreated and DF402-treated FUS transgenic mice. We found that at the early pre-symptomatic stage a limited number of genes significantly change expression in the spinal cord of transgenic mice and demonstrated that for 60% of these genes DF402 treatment causes the reversion of expression towards levels typical for expression of these genes in the spinal cord of wild type animals. Overall design: Deep RNA sequencing of thoracic and lumbar regions of spinal cord