ABSTRACT
Motoneuron degeneration leads to skeletal muscle denervation and impaired motor functions, yet the signals involved remain poorly understood. We find that extracellular ENGRAILED-1, a homeoprotein expressed in spinal cord V1 interneurons that synapse on α-motoneurons, has non-cell autonomous activity. Mice heterozygote for Engrailed-1 develop muscle weakness, abnormal spinal reflex and partial neuromuscular junction denervation. A single intrathecal injection of ENGRAILED-1 restores innervation, limb strength, extensor reflex and prevents lumbar α-motoneuron death for several months. The autophagy gene p62, which was found to network with Engrailed-1 and amyotrophic lateral sclerosis genes, is misregulated in Engrailed-1 heterozygote mice α-motoneurons and is rescued following ENGRAILED-1 injection. These results identify ENGRAILED-1 as an α-motoneuron trophic factor with long-lasting protective activity.
Footnotes
Conflict of Interest Statement: AP and KLM are on several patents for HP therapeutic use and co-founders of BrainEver. SEVA and ML are BrainEver post-doctorant and doctorant, respectively.
Funding sources: MemoLife Labex PhD fellowship to SEVA, Association Nationale de la Recherche et de la Technologie (Cifre/ANRT n° 2017/0488) to ML, BrainEver, HomeoSign ERC-2013-AdG n°339379.
This version of the manuscript has been condensed and shortened to comply with journal policy and a new section with new results has been added concerning p62, autophagy and EN1.
