Biology Reference
In-Depth Information
ABSTRACT
Axons depend critically on axonal transport both for supplying materials and for
communicating with cell bodies. This chapter looks at each activity, asking what
aspects are essential for axon survival. Axonal transport declines in neurodegen-
erative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, and
multiple sclerosis, and in normal ageing, but whether all cargoes are equally
affected and what limits axon survival remains unclear. Cargoes can be differen-
tially blocked in some disorders, either individually or in groups. Each missing
protein cargo results in localized loss-of-function that can be partially modeled
by disrupting the corresponding gene, sometimes with surprising results. The
axonal response to losing specific proteins also depends on the rates of protein
turnover and on whether the protein can be locally synthesized. Among cargoes
with important axonal roles are components of the PI3 kinase, Mek/Erk, and Jnk
signaling pathways, which help to communicate with cell bodies and to regulate
axonal transport itself. Bidirectional trafficking of Bdnf, NT-3, and other neuro-
trophic factors contribute to intra- and intercellular signaling, affecting the
axon's cellular environment and survival. Finally, several adhesion molecules
and gangliosides are key determinants of axon survival, probably by mediating
axon-glia interactions. Thus, failure of long-distance intracellular transport
can deprive axons of one, few, or many cargoes. This can lead to axon degenera-
tion either directly, through the absence of essential axonal proteins, or indi-
rectly, through failures in communication with cell bodies and nonneuronal
cells.
2011, Elsevier Inc.
I. INTRODUCTION
Axons are more autonomous than we used to think. They can synthesize proteins
locally (Giuditta
, 2002), degrade them (Korhonen and Lindholm, 2004),
replicate mitochondria (Amiri and Hollenbeck, 2008), carry out autophagy
(Yue
et al.
, 2008), form growth cones and respond to pathfinding cues
(Campbell and Holt, 2001; Gumy
et al.
, 2009), and even survive for several
weeks without their cell bodies when a single gene is altered (Mack
et al.
,2001).
When they do die, the mechanisms are distinct from those in cell bodies (Coleman,
2005). Ultimately, however, axons depend on two principle sources of support:
neuronal cell bodies and glia. This chapter shows howmolecular genetic studies are
identifying which axonal molecules are most essential for survival.
Axon survival depends on continuous axonal transport, the bidirection-
al transport of materials from and toward cell bodies. However, some axonal
transport cargoes are more essential than others, some have shorter half-lives
than others, and in many cases, transport of different cargoes is mediated by
et al.
