Biology Reference
In-Depth Information
Thus, axonal transport may have an optimum level such that too much
could be as damaging as too little. Axonal components need to be distributed
along the axon length not just delivered to the end, so failure to dissociate
cargoes from the transport machinery would prevent cargoes reaching the correct
destination just like failure to attach to transport machinery in the first place. A
unidirectional increase also risks a gradual buildup of excess components at one
end of the axon and a progressive deficiency at the other. Increased traffic may
wear out the “road” or saturate motor complexes needed for other cargoes. Our
understanding of how altered axonal transport leads to axon degeneration has
come a very long way in recent years, but these and many other intriguing
questions remain to be answered.
III. THE ESSENTIALS OF AXON SURVIVAL
Having established that axonal transport can be impaired in a cargo-specific
manner, it makes sense to ask which cargoes are most essential for axon survival.
Specific failure to deliver these would endanger axon survival more than when
less essential cargoes are blocked. Alternatively, when transport declines gener-
ally, as in ageing or with mechanical pressures, these are the cargoes whose
absence is most likely to precipitate axon degeneration. For individual proteins,
molecular genetic studies can help to identify which are the most critical, as
genetic disruption also stops their delivery to axons. Table 5.1 lists some proteins
in this category.
Interestingly, these proteins can be clustered into a relatively small
number of common themes that begin to tell us what functions are most critical
for axon survival. Around half are connected with axonal transport or vesicle
trafficking. Interestingly, not all motor proteins, scaffold proteins, or regulators of
axonal transport are essential for axon survival (see Table 5.2). Probably, the
motor proteins in Table 5.1 are those that carry essential cargoes. Microtubule
integrity clearly needs to be closely regulated by chaperones and severing pro-
teins as it probably influences all cargoes. Vesicle trafficking also clearly links to
axonal transport, and the likely involvement of lipid rafts in axonal delivery of
some membrane proteins illustrates how cholesterol and lipid metabolism could
also fit this theme (el-Husseini Ael and Bredt, 2002). Both protein synthesis and
degradation will influence the axonal levels of specific proteins, and the require-
ment for efficient protein degradation is also consistent with other reports that
proteasome inhibition is toxic to axons (Kane
, 2003). An
important role for adhesion molecules also emerges, probably mediating essential
axon-glia interactions (below).
et al.
, 2003; Laser
et al.
