TY - JOUR T1 - The homeoprotein ENGRAILED-1 promotes motoneuron survival and motor functions JF - bioRxiv DO - 10.1101/734020 SP - 734020 AU - Stephanie E. Vargas Abonce AU - Mélanie Lebœuf AU - Kenneth L. Moya AU - Alain Prochiantz Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/02/27/734020.abstract N2 - In addition to their cell-autonomous activities, a number of homeoprotein transcription factors transfer between cells and regulate gene transcription, protein translation and chromatin organization in a non-cell autonomous way. ENGRAILED-1 homeoprotein has the latter properties and is expressed in spinal cord V1 interneurons that synapse on large α-motoneurons. Because several homeoproteins have neuroprotective effects in the central nervous system, we analyzed the motor phenotype of mice with reduced extracellular spinal cord ENGRAILED-1 or lacking one functional Engrailed-1 allele. These mice show progressive muscle weakness, abnormal spinal reflex and partial neuromuscular junction denervation. In the Engrailed-1 heterozygote, large α-motoneuron degeneration is first observed at 4.5 months of age and progresses to reach 50 per cent loss in 15.5-month-old mice. A single intrathecal injection of exogenous recombinant human ENGRAILED-1 at 3 months in the lumbar enlargement of the heterozygote results in the addressing of the protein to α-motoneurons. This fully restores endplate innervation, limb strength and extensor reflex for at least 3 months, and prevents the death of lumbar α-motoneurons. Bioinformatic analysis identified the autophagy gene p62 as an Engrailed-1 target in spinal cord α-motoneurons and demonstrated both its upregulation in the heterozygote and its return to normal expression levels following ENGRAILED-1 injection. These results identify a direct non-cell autonomous activity of ENGRAILED-1 in spinal cord α-motoneuron survival and function and demonstrate that a single injection of the transcription factor in the Engrailed-1 heterozygote prevents α-motoneuron degeneration and strength loss for several months. ER -