Biology Reference
In-Depth Information
4.2. Axoprotection
Protection of retinal ganglion cell somas by itself would not be sufficient for
patients with optic neuropathies. A damaged axon will undergo axonal self-
destruction and therefore fail to conduct the electrical signals from the retina
that are necessary for vision. Protecting the retinal ganglion cell soma from
death is therefore insufficient for preserving visual function because loss of
the axon disconnects the retina from targets in the brain. Maintaining the
health of the retinal ganglion cell axon (i.e.,
axoprotection
) as well as the soma
is therefore critical for treating retinal ganglion cell axonal disease. A good
example of this is what occurs in Bax knockout mice. The retinal ganglion
cells in these animals fail to undergo apoptosis in optic nerve transection or
glaucoma, yet the axons fail to survive (
Howell et al., 2007; Libby et al.,
2005
).
A goal of many groups is to find therapeutic equivalents for axonal
degeneration, and this has been a topic of accelerating interest
(
Almasieh et al., 2011; Bechtold, Kapoor, & Smith, 2004; Bechtold
etal.,2006;Bei&Smith,2012;Fujinoetal.,2009;Fujita,Oda,Wei,&
Povlishock, 2011; Kitaoka et al., 2011; Waxman, 2005
). Much interest
in understanding the effects of axotomy has been the Wld
S
mouse, where
Wallerian degeneration is greatly slowed (
Lunn,Perry,Brown,Rosen,&
Gordon, 1989
), and distal neurites remain viable despite apoptosis of the
cell body (
Beirowski, Babetto, Coleman, & Martin, 2008; Deckwerth &
Johnson, 1994
). As expected, both Wallerian degeneration of the optic
nerve and retinal ganglion cell death are also slowed (
Perry et al., 1991
).
The molecular basis for Wld
S
is a fusion of nicotinamide mononucleotide
adenylyl transferase 1 (NMNAT-1) to ubiquitination factor e4b by an
18-amino-acid linkage. The mechanism of Wld
S
axoprotection involves
increased axonal NMNAT-1 after axotomy (
Babetto et al., 2010
).
NMNAT-1 is critical to synthesis of NAD
þ
, a key electron-accepting
redox agent, and it is possible that one of the redox reactions by which
elevated local NAD
þ
protects axons may be a target
for
future
axoprotection research.
It is unclear whether axoprotection related to a Wld
S
mechanism would
also be effective for retrograde degeneration. The Wld
S
genotype protects
against Wallerian but not retrograde axonal degeneration in the dopaminer-
gic nigrostriatal pathway (
Cheng & Burke, 2010
). This implies that there are
targets
for retrograde axoprotection may be different
from those for
Wallerian degeneration (
Kanamori et al., 2012
).
