Regulation of synaptic autophagy in motoneurons and its implication in motoneuron disease

Motoneuron diseases (MNDs) are characterized by progressive degeneration of motoneurons (MNs), resulting in muscle weakening and loss of motoric coordination. Despite decades of research, the pathophysiological mechanisms underlying MNDs are poorly understood. MNDs are characterized by misfolding, aggregation, and protein accumulation, leading to synaptic dysfunction and neuronal loss. Autophagy is one of the essential pathways for cellular quality control to remove damaged organelles, misfolded proteins, or protein aggregates. While autophagy is constantly active, physiologic changes, such as physical exercise, can modify autophagy levels in various tissues. We focused on two MND-associated genes: PLEKHG5 and SOD1. Whereas PLEKHG5 has been linked to several forms of lower MND, SOD1 mutations are associated with familial amyotrophic lateral sclerosis (ALS). This study aimed to unravel the pathophysiological mechanisms leading to vesicle accumulation and the involvement of physical exercise-derived autophagy induction in MNDs. The first part of the project focused on the clustering of presynaptic vesicles in Plekhg5-deficient mice. In the second part of this study, we focused on the involvement of Plekhg5 in the unconventional protein secretion of Sod1.