| Autor: |
Mishra PS; CERVO Brain Research Centre, 2601 Chemin de la Canardière, Quebec, QC G1J 2G3, Canada., Phaneuf D; CERVO Brain Research Centre, 2601 Chemin de la Canardière, Quebec, QC G1J 2G3, Canada., Boutej H; CERVO Brain Research Centre, 2601 Chemin de la Canardière, Quebec, QC G1J 2G3, Canada., Picher-Martel V; Division of Neurosciences, Centre Hospitalier Universitaire de Québec, Laval University, Quebec, QC G1V 4G2, Canada., Dupre N; Division of Neurosciences, Centre Hospitalier Universitaire de Québec, Laval University, Quebec, QC G1V 4G2, Canada., Kriz J; CERVO Brain Research Centre, 2601 Chemin de la Canardière, Quebec, QC G1J 2G3, Canada.; Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Quebec, QC G1V 0A6, Canada., Julien JP; CERVO Brain Research Centre, 2601 Chemin de la Canardière, Quebec, QC G1J 2G3, Canada.; Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Quebec, QC G1V 0A6, Canada. |
| Abstrakt: |
The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few years ago, we reported that the cerebrospinal fluid (CSF) from sporadic ALS patients contains toxic factors for disease transmission in mice via chronic intracerebroventricular (i.c.v.) infusion. Thus a 14-day i.c.v. infusion of pooled CSF samples from ALS cases in mice provoked motor impairment as well as ALS-like pathological features. This offers a unique paradigm to test therapeutics in the context of sporadic ALS disease. Here, we tested a new Withaferin-A analog (IMS-088) inhibitor of NF-κB that was found recently to mitigate disease phenotypes in mouse models of familial disease expressing TDP-43 mutant. Our results show that oral intake of IMS-088 ameliorated motor performance of mice infused with ALS-CSF and it alleviated pathological changes including TDP-43 proteinopathy, neurofilament disorganization, and neuroinflammation. Moreover, CSF infusion experiments were carried out with transgenic mice having neuronal expression of tagged ribosomal protein (hNfL-RFP mice), which allowed immunoprecipitation of neuronal ribosomes for analysis by mass spectrometry of the translational peptide signatures. The results indicate that treatment with IMS-088 prevented many proteomic alterations associated with exposure to ALS-CSF involving pathways related to cytoskeletal changes, inflammation, metabolic dysfunction, mitochondria, UPS, and autophagy dysfunction. The effective disease-modifying effects of this drug in a mouse model based on i.c.v. infusion of ALS-CSF suggest that the NF-κB signaling pathway represents a compelling therapeutic target for sporadic ALS. |
