COMPOUNDS FOR USE IN THE TREATMENT OF DISEASES ASSOCIATED WITH ALTERED AUTOPHAGY, ALTERED SHH TRANSDUCTION, AND/OR NEURODEGENERATIVE DISEASES

摘要

The present invention relates to the prevention and/or the treatment of a disease associated with altered autophagy and/or Shh transduction, such as a cancer, an immune disease, an infectious disease, a metabolic disease, a cardiovascular disease, a (cardio)myopathy, heart failure, a lysosomal disease, spinal cord injury and trauma, a neurodegenerative disease and a pulmonary disease. The inventors showed that Gigaxonin promotes the fine-tuning of autophagy, by the means of its interaction with ATG16L1. In particular, cells depleted of Gigaxonin (GAN^-/^- neurons) exhibit ATG16L1 aggregation and a reduced capacity to produce autophagosomes, whereas overexpression of Gigaxonin rescues ATG16L1 aggregation and restores autophagy flux in GAN^-/^- neurons. The inventors also demonstrate that Gigaxonin is a key positive regulator of the Shh pathway, enabling receiving cells to convey signaling into motility. In particular, Gigaxonin depletion inhibits Shh transduction in the gan zebrafish model and patient cells, through a mechanism involving the interaction and degradation of the PTCH receptor. This pinpoints to an evolutionary-conserved and reversible mechanism that controls the entry point of Shh signalling and to the developmental origin of GAN. Thus, the present invention relates to a modulator of the expression, stability, degradation and/or activity of Gigaxonin, of the Gigaxonin/ATG16L1 or PTCH interaction and/or of the functionality of the Gigaxonin/ATG16L1 or PTCH interaction, for the prevention and/or the treatment of a disease associated with altered autophagy, Shh signaling and/or neurodegenerative disease.