Biology Reference
In-Depth Information
is pathogenic. Given that the highest density of aquaporin-4 is at astrocyte
endfeet at the blood-nerve barrier and that antibodies to aquaporin-4
increase blood-brain barrier permeability (
Vincent et al., 2008
), increased per-
meability may be a critical event in this inflammatory disease. More recently, it
has been shown that the Sonic hedgehog pathway regulates blood-brain bar-
rier permeability and it has been suggested that this could be a focal point for
inflammatory disease in the central nervous system (
Alvarez et al., 2011
).
3. AXONAL DEGENERATION
Axonal degeneration after injury takes place in two directions, one
toward the proximal cell body (retrograde degeneration) and the other
toward the distal axon terminal (Wallerian or orthograde degeneration).
Most advances in the science of axonal degeneration have focused on
Wallerian degeneration (
Coleman & Freeman, 2010
).
The processes of soma death and axon degeneration are independent
(
Raff, Whitmore, & Finn, 2002
), and our understanding of retinal ganglion
cell axonal degeneration lagged behind that of retinal ganglion cell apoptosis
for many years. One of the reasons is that there are relatively fewmethods for
investigating axon loss in the nervous system over time with sufficient spatial
and temporal resolution. More recently, mechanisms of central axonopathy
have become the subject of burgeoning investigation. Axonal responses can
be divided into (1) those associated with how the axon locally responds to
injury and (2) those associated with degeneration of the proximal and distal
healthy axon as a result of the injury.
1.
Mechanisms for direct axonal damage include excess accumulation of
Ca
2
þ
ions, activation of calpains, loss of the membrane potential, and
other processes. In healthy fibers, ATP-dependent pumps support ho-
meostasis of ionic gradients. When energy supply is limited, either
due to inadequate delivery or due to excessive utilization, ion gradients
break down, unleashing a variety of cascades leading to Ca
2
þ
overload,
activation of destructive enzymes, and local axonal dissolution (
George,
Glass, & Griffin, 1995
).
2.
Mechanisms for degeneration of the healthy axon after injury are differ-
ent, with most research focusing on loss of the distal segment, that is,
Wallerian degeneration. Similar to the self-destruct program for apopto-
sis, neurons have a molecularly distinct self-destruct program in their
axon (
Raff et al., 2002
). This program is activated when the axon is sev-
ered and leads to the rapid degeneration of the isolated part of the cut
