Regulation of synaptic autophagy in motoneurons and its implication in motoneuron disease

• Applicant: Dr. Patrick Lüningschrör
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427708959

Autophagy is an essential cellular quality control mechanism to remove damaged organelles, misfolded proteins or protein aggregates. During autophagy, cytoplasmic materials are sequestered into a double-membraned autophagosome, which finally fuses with a lysosome enabling degradation of cargos. Most neuronal autophagosomes are generated in the distal compartment of the axon. Newly synthesized autophagosomes are transported retrogradely along the axon towards the soma, where they mature and fuse with lysosomes. Autophagy-mediated degradation of synaptic components is involved in several physiological processes but also represents a mechanism of neurodegeneration.We have recently identified autophagy-mediated turnover of synaptic vesicles at neuromuscular junctions as a pathogenic mechanism in motoneuron disease. Autophagy of synaptic vesicles is regulated by the guanine exchange factor (GEF) pleckstrin homology containing family member 5 (Plekhg5). Different mutations within the PLEKHG5 gene have been linked to distinct forms of motoneuron disease. Plekhg5 modulates autophagy of synaptic vesicles via its function as a GEF for Rab26, a small GTPase that directs synaptic vesicles to pre-autophagosomes.The aim of this proposal is to study the regulation of Plekhg5-mediated synaptic vesicle turnover and to characterize the synaptic vesicle subset that is delivered to autophagosomes for degradation. We hypothesize that neuronal activity regulates autophagy in motoneurons and possibly also other types of neurons and that neuronal activity triggered by physical exercise represents a mechanism to modulate presynaptic autophagy in motoneurons in a Plekhg5-dependent manner. In several brain regions, synaptic activity upregulates the expression of BDNF, a major regulator of synaptic plasticity. BDNF also regulates neuronal autophagy for stabilization of synaptic contacts. We would like to study a potential role of BDNF in regulating Plekhg5-mediated autophagy in motoneurons in vitro and in vivo. In a second step, we will characterize the subpopulation of synaptic vesicles designated for autophagy-mediated degradation. We aim to determine at which step during their cycle defective synaptic vesicles are recognized and removed. Our expected results are thus important for a better understanding of synaptic vesicle turnover and its role in the pathophysiology of motoneuron disease.

• DFG Programme: Research Grants