Stop-and-go: exploring canonical and non-canonical functions of autophagy at mammalian cortical en passant synapses

• Applicant: Professorin Dr. Natalia Kononenko
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 493153982

Neurons maintain axonal homeostasis via employing a unique organization of microtubule (MT) cytoskeleton, which supports axonal morphology and provides tracks for intracellular transport. Abnormal MT-based trafficking hallmarks the pathology of neurodegenerative diseases, but the exact mechanism regulating MT dynamics in neurons remains enigmatic. My recent data highlight a novel regulation of MT dynamics by autophagy, a natural cellular pathway previously linked to the removal of dysfunctional proteins and organelles. We found that AuTophaGy(ATG)-related proteins regulate MT stability in cortical en passant synapses. This function of ATGs is independent of their role in protein degradation and requires the presynaptic active zone protein ELKS1. These findings unravel a previously unknown role for ATG proteins in neurons and suggest a model according to which autophagy might function at presynapses to temporally adjust the local MT dynamics to intense cycles of neuronal activity. How ATG proteins switch from their canonical function in protein degradation to regulation of MT dynamics at en passant synapses is currently unknown. Equally unknown are the physiological conditions triggering the MT remodeling at en passant active zones by autophagy and its relevance for presynaptic physiology. Both questions will be addressed in the current research proposal. On the long run, I believe that the results streaming out of this project will lay the groundwork for understanding neuropathological conditions with synaptic malfunctions and facilitate the identification of new therapeutic targets in neurodegeneration.

• DFG Programme: Research Grants