Axonal Degeneration in Retinal Ganglion Cells Is Associated with a Membrane Polarity-Sensitive Redox Process

作者：Almasieh Mohammadali; Catrinescu Maria Magdalena; Binan Loic; Costantino Santiago; Levin Leonard A^*

来源：Journal of Neuroscience, 2017, 37(14): 3824-3839.

DOI：10.1523/JNEUROSCI.3882-16.2017

• axon membrane
• axonal degeneration
• phosphatidylserine
• redox
• Wallerian degeneration slow

Axonal degeneration is a pathophysiological mechanism common to several neurodegenerative diseases. The slow Wallerian degeneration (WldS) mutation, which results in reduced axonal degeneration in the central and peripheral nervous systems, has provided insight into a redox-dependent mechanism by which axons undergo self-destruction. We studied early molecular events in axonal degeneration with single-axon laser axotomy and time-lapse imaging, monitoring the initial changes in transected axons of purified retinal ganglion cells (RGCs) from wild-type and Wld(S) rat retinas using a polarity-sensitive annexin-based biosensor (annexin B12-Cys101, Cys260-N, N'-dimethyl- N-(iodoacetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) ethylenediamine). Transected axons demonstrated a rapid and progressive change in membrane phospholipid polarity, manifested as phosphatidylserine externalization, which was significantly delayed and propagated more slowly in axotomized Wld(S) RGCs compared with wild-type axons. Delivery of bis(3-propionic acid methyl ester) phenylphosphine borane complex, a cell-permeable intracellular disulfide-reducing drug, slowed the onset and velocity of phosphatidylserine externalization in wild-type axons significantly, replicating the WldS phenotype, whereas extracellular redox modulation reversed the Wld(S) phenotype. These findings are consistent with an intra-axonal redox mechanism for axonal degeneration associated with the initiation and propagation of phosphatidylserine externalization after axotomy.

• 出版日期2017-4-5
• 单位McGill