Synaptic autophagy: a common culprit in Parkinson's disease

Parkinson’s disease (PD) is without a cure and in its earliest phases, it is characterized by synaptic dysfunction and protein aggregation. However, the underlying mechanisms are elusive. Based on pathogenic mutations causative to familial PD, we have uncovered a process critical for synaptic protein turnover: “synaptic autophagy”. While synaptic autophagy uses some of the core components of classical autophagy, it is fundamentally different, and under control of several synapse specific proteins mutated or risk factors in PD. Our hypothesis is that synaptic autophagy defects are common to familial PD. Using a unique collection of >70 isogenic knock in fruit flies we will now assess synaptic autophagy across the genetic space of PD. This collection also includes a new PD gene that we recently identified and tightly binds EndoA, suggesting it also acts in synaptic autophagy. We will use new innovative tools (eg blue light dimerization of α-synuclein) to study synaptic autophagy, both in fruit flies and in induced human neurons. Finally, we will also use spatially resolved proteomic mapping (APEX2a) to identify new proteins implicated in the process. We will communicate their identity to neurologists and geneticists (GeneMatcher), as to identify novel human mutations related to PD in the proteins we identified. Our work not only has the capacity to uncover novel aspects in the regulation of presynaptic function, but it will also reveal mechanisms of synaptic