Non-canonical role of macroautophagy in neurotrophin signalling and axonal homeostasis

• Applicant: Professorin Dr. Natalia Kononenko
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 354726740

Macroautophagy is thought to provide nutrients during starvation and to eliminate defective proteins and organelles to protect cells from damage. Defective macroautophagy hallmarks the pathology of neurodegenerative disorders, while neuronal confined knockout (KO) of several AuTophaGy (ATG)-related genes causes neurodegeneration. How precisely ATG proteins regulate brain function and promote neuronal survival is currently unknown. In neurons autophagosomes form locally in distal axons and are trafficked retrogradely to the neuronal soma. My recent data indicate that this trafficking route is exploited by BDNF/TrkB signaling endosomes to mediate the neuronal complexity. Neurons lacking the crucial autophagy protein ATG5 reveal severe impairment of BDNF/TrkB signalling, a phenotype accompanied by the surprising overall loss of TrkB receptors and selective degeneration of axons. These findings imply to a previously unknown role for autophagosomes in TrkB signaling and maintenance of neuronal function. Therefore, based on these results I suggest that ATG proteins in neurons fulfill an additional non-canonical function and regulate neuronal homeostasis via mediating the BDNF/TrkB signalling, a hypothesis that I will dissect in detail in the current project. To dissect the precise cellular and molecular mechanism by which autophagy regulates the activation and trafficking of TrkB receptors I will focus on two crucial autophagy proteins ATG5 and ATG16L1. Using tamoxifen inducible ATG5 and Atg16L1 KO mouse lines and applying a combination of genetic, molecular, in-vivo neuroanatomical and imaging tools I will probe whether autophagosomes control the intracellular sorting and trafficking of neurotrophin receptors. Furthermore, I will examine the role of autophagy in selective axonal neuropathy and test whether autophagy-loss-of-function -induced defective intracellular Ca2+-homeostasis underlies the selective degeneration of axons in ATG5 KO mice. Finally, by applying the rescue approaches I will probe if in-vivo BDNF delivery rescues the loss of neurons and prolongs the life span of autophagy deficient mice. On the long run I believe that the results streaming out from this project will lay the groundwork for understanding the neuropathological conditions in which autophagy and neurotrophin signaling malfunction and facilitate the identification of new therapeutic targets in neurodegeneration.

• DFG Programme: Research Grants