PLEKHM2 Participates in iPSC-derived Neuron Function through Autophagic Flux Regulation

Hadas Ben-Zvi ¹ Tatiana Rabinski ² Rivka Ofir ^2,3 Smadar Cohen ^1,2,4 Gad D Vatine ^2,5,6

¹The Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Israel
²The Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Israel
³Dead Sea & Arava Science Center, Ben-Gurion University of the Negev, Israel
⁴Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Israel
⁵The Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Israel
⁶The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Israel

Autophagy is a highly conserved process responsible for pathogen, protein and cellular component degradation, thereby maintaining cellular homeostasis. Since autophagy plays a crucial role in homeostasis, autophagic dysregulation was associated with neurodegenerative pathogenesis and therefore its modulation holds a considerable potential as a therapeutic target. PLEKHM2 is one of many proteins involved in the regulation of autophagy. The autophagosome and lysosome are the two executing organelles in autophagy, the former envelops component for disintegration, and the latter carries digestion. Interactions with PLEKHM2 mediates lysosomal transport to the cell periphery.

Mutated PLEKHM2 (mPLEKHM2) was found to induce a severe cardiovascular disorder named dilated cardiomyopathy with left ventricular non-compaction (DCM-LVNC), resulting in a premature death due to heart failure. Here, we hypothesized that PLEKHM2 participates in neuronal development and function. We used patient-specific mPLEKHM2 induced pluripotent stem cell (iPSC) to examined whether PLEKHM2 influences motor neurons (iMNs) development and function. While differentiation potential was not affected, mPLEKHM2-iMNs exhibited reduced autophagic activity, delayed functional maturation and more frequent and unsynchronized electrophysiological activity. This was associated with increased size and a more perinuclear lysosome cellular distribution. Thus, our results suggest that PLEKHM2 is involved in functional development of neurons through regulation of autophagic flux.