title: Proteasome inhibitors to alleviate aberrant IKBKAP mRNA splicing and low IKAP/hELP1 synthesis in familial dysautonomia.
abstract: FD is a rare neurodegenerative disorder caused by a mutation of the IKBKAP gene, which induces low expression levels of the Elongator subunit IKAP/hELP1 protein. A rational strategy for FD treatment could be to identify drugs increasing IKAP/hELP1 expression levels by blocking protein degradation pathways such as the 26S proteasome. Proteasome inhibitors are promising molecules emerging in cancer treatment and could thus constitute an enticing pharmaceutical strategy for FD treatment. Therefore, we tested three proteasome inhibitors on FD human olfactory ecto-mesenchymal stem cells (hOE-MSCs): two approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), bortezomib and carfilzomib, as well as epoxomicin. Although all 3 inhibitors demonstrated activity in correcting IKBKAP mRNA aberrant splicing, carfilzomib was superior in enhancing IKAP/hELP1 quantity. Moreover, we observed a synergistic effect of suboptimal doses of carfilzomib on kinetin in improving IKBKAP isoforms ratio and IKAP/hELP1 expression levels allowing to counterbalance carfilzomib toxicity. Finally, we identified several dysregulated miRNAs after carfilzomib treatment that target proteasome-associated mRNAs and determined that IKAP/hELP1 deficiency in FD pathology is correlated to an overactivity of the 26S proteasome. Altogether, these results reinforce the rationale for using chemical compounds inhibiting the 26S proteasome as an innovative option for FD and a promising therapeutic pathway for many other neurodegenerative diseases.
authors.affiliation: Aix-Marseille Univ, CNRS, CRN2M, 13344 Marseille Cedex 15, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Hervé
authors.affiliation: Aix-Marseille Univ, CNRS, CRN2M, 13344 Marseille Cedex 15, France; Aix-Marseille Univ, CNRS, INT, Inst Neurosci Timone, 13385 Marseille Cedex 5, France. Electronic address: el-cherif.ibrahim@univ-amu.fr.
authors.forename: El Chérif
authors.initials: EC
authors.lastname: Ibrahim
mesh_terms: D000069286:Bortezomib / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004402:Dysautonomia, Familial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D012326:RNA Splicing / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D035602:Transcriptional Elongation Factors; D000069286:Bortezomib
keywords: Carfilzomib; Familial dysautonomia; IKBKAP; MicroRNA; Proteasome; mRNA splicing