The homeoprotein ENGRAILED-1 promotes motoneuron survival and sustains motor functions

Abstract

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 is endowed with the latter properties and is expressed in spinal cord V1 inhibitory interneurons that synapse on large spinal cord α-motoneurons. Based on the neuroprotective effects of several homeoproteins in the adult central nervous system, we have analyzed the motor phenotype of mice lacking one functional Engrailed-1 allele. Engrailed-1 heterozygote mice with Engrailed-1 expression reduced by half in the spinal cord start to show muscle weakness, abnormal spinal reflex and partial neuromuscular junction denervation between 2 and 3 months of age. Alpha-motoneuron degeneration is first observed at 4.5 months and progresses with time, reaching 50 per cent in 15.5-month-old mice. A single intrathecal injection of exogenous recombinant human ENGRAILED-1 at 3 months in the lumbar enlargement allows for an addressing of the protein to lumbar α-motoneurons and, to a lesser degree, to cervical ones. This results in full restoration of strength and extensor reflex for at least 2 months, in parallel with a preservation of the number of lumbar α-motoneurons, and blocks endplate denervation. The similarities of the Engrailed-1 heterozygote phenotype to motor neuron disease symptoms and the long-lasting effects of a single ENGRAILED-1 injection suggests that this approach may be of interest in the search for therapies alleviating the consequences of α-motoneuron degeneration.