Regulation of synaptic autophagy in motoneurons and its implication in motoneuron disease
Cell Biology
Final Report Abstract
Dysfunction of presynaptic autophagy is a pathophysiological mechanism in motoneuron disease (MND), which leads to impaired synaptic integrity and function. Thus, further understanding the mechanisms regulating presynaptic autophagy might give insight into the underlying pathophysiological mechanisms and could potentially be harnessed to identify novel therapeutic targets. Synaptic vesicles (SVs) are targeted to autophagosomes by the small GTPase Rab26, which is enriched on a subset of SVs. The guanine exchange factor Plekhg5 (Pleckstrin homology domain containing family G) regulates the activity of Rab26. Mutations in the human PLEKHG5 gene have been linked to different forms of lower MND. Depletion of Plekhg5 in mice leads to an MND with marked vesicle accumulations at motoneuron (MN) terminals, in peripheral nerves, and within the spinal cord. As part of the project, we characterized the vesicle accumulations in more detail and investigated the link between MN activity and presynaptic autophagy. We found marked accumulations of Atg9- containing vesicles at presynaptic sites of Plekhg5-deficient mice, which could be cleared by four weeks of voluntary running wheel exercise in young but surprisingly not in aged Plekhg5- deficient mice. However, physical exercise in aged mice led to synaptic vesicle sorting into the Atg9-containing vesicle accumulations without their removal. In line with these findings, shortterm voluntary exercise triggered motoneuron autophagy in young but not old mice. Furthermore, we found an expected link between Sod1 and Plekhg5. Deletion of Plekhg5 in mice leads to the accumulation of Sod1 in lysosomal-related organelles (LROs) at swollen presynaptic sites. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory LROs before releasing Sod1 into the extracellular milieu. In conclusion, we could unravel an unexpected pathophysiological mechanism that converges two MND-associated proteins into a common pathway. Furthermore, we identified that the Plekhg5-mediated form of presynaptic autophagy is uncoupled from neuronal activity. Physical exercise provides a means to bypass this block. Thus, boosting autophagy by physical exercise might provide a tool to maintain presynaptic function at the early but not late stages of Plekhg5-associated MND and possibly ALS.
Publications
-
Absence of Plekhg5 Results in Myelin Infoldings Corresponding to an Impaired Schwann Cell Autophagy, and a Reduced T-Cell Infiltration Into Peripheral Nerves. Frontiers in Cellular Neuroscience, 14.
Lüningschrör, Patrick; Slotta, Carsten; Heimann, Peter; Briese, Michael; Weikert, Ulrich M.; Massih, Bita; Appenzeller, Silke; Sendtner, Michael; Kaltschmidt, Christian & Kaltschmidt, Barbara
-
Calnexin controls TrkB cell surface transport and ER-phagy in mouse cerebral cortex development. Developmental Cell, 58(18), 1733-1747.e6.
Lüningschrör, Patrick; Andreska, Thomas; Veh, Alexander; Wolf, Daniel; Giridhar, Neha Jadhav; Moradi, Mehri; Denzel, Angela & Sendtner, Michael
-
Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy. Nature Communications, 15(1).
Hutchings, Amy-Jayne; Hambrecht, Bita; Veh, Alexander; Giridhar, Neha Jadhav; Zare, Abdolhossein; Angerer, Christina; Ohnesorge, Thorben; Schenke, Maren; Selvaraj, Bhuvaneish T.; Chandran, Siddharthan; Sterneckert, Jared; Petri, Susanne; Seeger, Bettina; Briese, Michael; Stigloher, Christian; Bischler, Thorsten; Hermann, Andreas; Damme, Markus; Sendtner, Michael & Lüningschrör, Patrick
