Biology Reference
In-Depth Information
Other mRNAs in both mammalian and
axons cluster around certain
types of protein, in particular, those encoding protein translation machinery,
cytoskeletal proteins, proteasome subunits, mitochondrial proteins, and heat
shock proteins (Gumy
Aplysia
et al.
, 2009; Moccia
et al.
, 2003; Willis
et al.
, 2007),
together with some membrane and secreted proteins (Merianda
, 2009).
However, mRNAs encoding many of the essential proteins listed in Table 5.1 are
conspicuously absent from the list of axonal mRNAs reported so far (Willis
et al.
,
2007). Thus, axonal protein synthesis does not in general appear to be designed
to supply essential proteins that axonal transport fails to deliver. Instead, its main
function may be to facilitate a rapid axonal response to local events such as
trauma, neurotrophic signaling, or pathfinding cues (Campbell and Holt, 2001;
Gumy
et al.
, 2009).
Nevertheless, there are indications that local protein synthesis does
influence axon survival. First, spinal muscular atrophy, a lower motor neuron
disease with early axon loss (Cifuentes-Diaz
et al.
, 2002), is caused by loss-of-
function mutations in the survival motor neuron (smn) protein. Although there
is some controversy, the essential function of smn does seem to be axonal, where
it helps deliver mRNA for
et al.
, 2007).
Second, glycyl tRNA synthetase, a tRNA-charging enzyme whose loss-of-
function causes Charcot-Marie-Tooth Disease Type 2D, is abundant in periph-
eral axons where it seems likely to function in local synthesis.
-actin (Carrel
et al.
, 2006; Conforti
et al.
VII. ANTEROGRADE SURVIVAL SIGNALING
Together, the preceding sections tell us that (a) a subset of axonal proteins are
critically important for survival, (b) some protein half-lives appear barely com-
patible with delivery to distal axons before these proteins degrade, and (c) a
largely nonoverlapping subset of axonal proteins can be locally translated in
axons. When delivery of many cargoes is impaired, those that limit axon survival
are likely to be essential, short-lived, and unable to be locally synthesized
(Fig. 5.4). Essential proteins with longer half-lives will remain abundant in
axons until the dwindling supply of short-lived, essential proteins has already
killed the axon. Locally synthesized proteins could be maintained for as long as
the translation machinery remains active, which could be a long time if the
protein synthesis machinery can be supplied by associated glia, as recently
proposed (Court
, 2008). Thus, when the supply of specific cargoes fails,
the life or death of an axon, and whether it dies quickly or slowly, will depend on
whether the affected cargo is in this central category.
One example of such a protein has recently been reported. The NAD
รพ
biosynthesis enzyme nicotinamide mononucleotide adenylyltransferase
2 (Nmnat2) is a highly labile molecule whose presence in axons, at least in
et al.
