期刊
JOURNAL OF NEUROSCIENCE
卷 37, 期 14, 页码 3824-3839出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3882-16.2017
关键词
axon membrane; axonal degeneration; phosphatidylserine; redox; Wallerian degeneration slow
资金
- Canadian Foundation for Innovation
- Canada Research Chair Program
- National Institutes of Health [R21 EY025074, P30EY016665]
- Research to Prevent Blindness
- Natural Sciences and Engineering Research Council of Canada
- Fonds de Recherche du Quebec-Sante
- Fonds de Recherche en Ophtalmologie de l'Universite de Montreal
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.
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