Proteostasis relies on the proper balance between protein synthesis and degradation. Molecular chaperones, the ubiquitin-proteasome system (UPS), and autophagy represent the main routes for protein degradation. Neurons, as postmitotic cells that cannot dilute out any superfluous material, depend on those mechanisms for their function and/or survival. Autophagy is not only required for the survival of certain neuronal populations but is also implicated in higher cognitive functions. Neuronal autophagy is initiated in the distal axon under basal conditions. In my first Ph.D. project, we show that autophagic vesicle biogenesis is induced locally in post-synaptic dendrites upon long-term depression (LTD), a major form of long-term plasticity mediated via the NMDA- or mGluRs. We demonstrated that autophagy is a prerequisite in the post-synapse for the degradation of core postsynaptic proteins that mediate the functional and structural changes of LTD. Electrophysiological experiments showed that LTD is abolished after genetic or pharmacological blockage of autophagy in the postsynaptic compartment of excitatory neurons, while unbiased mass spec analysis indicated that several postsynaptic proteins are cargo of autophagic degradation. Thus, this work sheds light on the interplay between autophagy and the core mechanisms of synaptic plasticity that underlie key cognitive functions.
Except for the role of autophagy in degradation, core autophagy proteins have been suggested to serve non-degradative functions, however these functions have not yet been described in neurons. Here, we provide evidence that ATG101, an autophagy protein of the ULK1 complex, has non-canonical functions in neurons. We show that ATG101 is enriched in neurons, as compared to other brain cells. We generated the first hypomorphic atg101 animal, which exhibited normal brain autophagic flux, yet presented with neurological deficits and spontaneous epileptic seizures. Further analysis indicated impaired RNA processing as well as mitochondrial deficits. Therefore, a novel role of ATG101 is suggested that may be associated with the yet undescribed nuclear shuttling of this protein. Future experiments will reveal the role of ATG101 in brain function and neuronal homeostasis.