HOW DOES AUTOPHAGY COPE WITH SPECIFIC SYNAPTIC NEEDS? CONSEQUENCES IN BRAIN HEALTH AND DISEASE

Synapses are the communication center of the neuron and to secure their metabolic demand and to avoid accumulation of toxic components during intense neuronal communication and development, synapses locally recycle proteins, lipids and even organelles. At the synapse, the regulation of macroautophagy, hereafter called autophagy has compartment-specific mechanisms to degrade and recycle cellular components to support synaptic function and deregulation of synaptic autophagy can impair synaptic homeostasis and jeopardize neuronal survival. Defects in autophagy, together with aberrant protein and lipid accumulation, are present during aging and in neurodegenerative diseases, but how defects in synaptic autophagy are mechanistically linked to synaptic dysfunction, decay and neuronal loss are not fully understood.
Our work shows that autophagy is locally regulated at presynaptic terminals by a set of synaptic proteins. We also started to decipher that besides aminoacid starvation, a common activator of autophagy in most body cells, synaptic activity is crucial to activate autophagy at the presynaptic terminal. Unfortunately, most of the studies focus on how aminoacid deprivation activates autophagy. We will present unique characteristics of synaptic autophagy and data that demonstrate the existence of molecular distinct synaptic autophagy pathways. Furthermore, We will show that under physiological conditions different autophagy pathways execute different functions to support the neuron. Under pathological conditions in the context of Frontotemporal dementia this is particularly relevant since we identified a specific autophagy pathway that functions in the degradation of pathological Tau.