in particular aging of post-mitotic neurons, is an essential contributor to neurodegeneration development. Indeed, the majority of neurodegenerative diseases only become symptomatic in late adulthood, even when genetically driven in individuals carrying the causative mutations since birth. Neural activity is energy-consuming as illustrated by the fact that the human brain, which accounts for only 2% of total body weight, consumes 20% of the daily body energy production. Energy consumption is particularly important in neurons presenting high spiking activity and/or long projections. Among these high consuming populations, one finds midbrain dopaminergic neurons, spinal cord alpha motor neurons, retinal ganglion cells and photoreceptors which degenerate in Parkinson Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Glaucoma and Age-related Macular Degeneration (AMD), respectively.

Energy (ATP) production is paralleled with that of toxic reactive oxygen species (ROS), progressively leading to heterochromatin disorganization, genomic instability and DNA breaks. These activity-associated changes are physiological and normally repaired by the cells. But with age, even in the absence of neurodegenerative pathology (healthy aging), there is a progressive degradation of the repair systems until a threshold is reached, when compensation is no longer possible, and symptoms of neuronal dysfunction appear. In neurodegenerative diseases, causative mutations and/or specific environmental factors are responsible for an early crossing of this threshold.

Homeoproteins (HPs)

A major discovery made by Prochiantz’ group is that HPs are also signaling factors transferring between cells thanks to unconventional secretion and internalization signal peptides highly conserved among the 300 existing mammalian HPs (Lee et al. 2020). Following internalization, HPs are directly addressed to the cytoplasm and nucleus of recipient cells, where they regulate several important cellular functions, including gene transcription, protein translation and epigenetic maintenance (reviewed in Di Nardo et al., 2018; 2020). Interestingly, HPs have the capacity to reverse cellular aging by restoring a more juvenile and stable epigenetic chromatin status, reducing DNA breaks and halting cell death. The first two HPs in BrainEver’s pipeline are human ENGRAILED-1 (hEN1) and human OTX2 (hOTX2) developed for the treatment of ALS, PD, Glaucoma and AMD.