EEN SYNAPS SPECIFIEK MECHANISME DAT SYNAPSTISCHE GEZONDHEID ONDERHOUDT IS BETROKKEN IN DE ZIEKTE VAN PARKINSON

The human brain consists of around 86 billion neurons. At one end of a neuron resides a largely independent compartment, called a synapse. Synapses are often located far from its cell body. These presynaptic terminals are essential for transfer of information from one neuron to the other. This flow of information as a result of neuronal activity can induce proteopathic stress where a synapse needs to cope with in an independent manner. However, how synapses turn over proteins and what the underlying molecular mechanisms are is poorly understood. In this work, we have focused on dissecting these underlying molecular mechanisms to maintain synaptic health, especially with regards to Parkinson’s disease (PD). In a first part, we generated a novel fast and efficient method to manipulate the genome in the endogenous gene locus of Drosophila melanogaster. Genetically manipulating genes in their endogenous locus offers many advantages over the traditional overexpression methods, the most important one being to asses gene function depending on its own genomic environment. In a second part, we reveal that macroautophagy occurs at synapses and that the most commonly mutated gene in PD, LRRK2 and its phosphorylation target EndophilinA (EndoA) are necessary in this process by recruiting Atg3. In addition, we show that also Synaptojanin1 (SYNJ1), another PD-gene, is required for autophagosome formation at presynaptic terminals by dephosphorylation of PI(3)P and PI(3,5)P2, promoting Atg18a mobility at synaptic autophagosomes. Interestingly, by utilizing specific point mutations in LRRK2, EndoA and SYNJ1, we connect proteins previously described in endocytosis with a new function in synaptic autophagy. Taken together, this work reveals a new synapse specific pathway that maintains synaptic health with relevance to Parkinson’s disease. Paving the way for possible new therapeutic strategies and drug discovery.nrpages: 235status: publishe