Biology Reference
In-Depth Information
IV. TAKE IT OR LEAVE IT: WHAT AXONS DO NOT NEED TO SURVIVE
Conversely, there are many proteins whose functional absence has little effect on
axon survival (Table 5.2). Null mouse or
studies, especially when limited
to early developmental stages, cannot of course rule out degeneration over the
longer term in larger human axons, but failure to deliver these proteins to axons does
not precipitate axon degeneration within the confines of the experimental system
listed. Some have other functional consequences, but axons survive.
There are a number of surprises in this list. Axons can survive in the
absence of proteins essential for synaptic function, without some of their most
abundant proteins, or without proteins closely associated with neurodegenera-
tive diseases.
Redundancy is one obvious explanation why axons survive without
some proteins. For example, mice lacking tau show no obvious axonal defects
(Dawson
Drosophila
, 2008), but when Map1b is also removed, the
axonal phenotype is far worse than for either individual deletion (Takei
et al.
, 2001; Yuan
et al.
,
2000). In this particular example, the question whether this is a degenerative
phenotype as well as developmental still needs to be resolved, but it illustrates
the point that the function of some axonal proteins can be filled by others.
Synaptic vesicle trafficking and function can be impaired without
compromising axon survival. Rab3 proteins, a family of GTP-binding proteins
with seemingly ubiquitous roles in vesicular transport, have essential roles in
evoked release of synaptic vesicles. Structurally, however, there is no apparent
change in brain or synapse structure even when all four isoforms are deleted
simultaneously in mice (Schluter
et al.
et al.
, 2004).
Drosophila
embryos deficient in
Imac
, a kinesin 3 protein essential for synaptic vesicle transport, develop axons
that contact their muscles, even if they lack extended branches and mature
synapses (Pack-Chung
and mouse axons can
develop without any signs of degeneration in the absence of synaptotagmin
(Geppert
et al.
, 2007), and both
Drosophila
, 2001). Thus, while some aspects of vesicle
trafficking are essential for axon survival (Table 5.1), profound defects in synap-
tic vesicle trafficking or function do not necessarily cause axon degeneration.
Axons are also remarkably tolerant of disruptions to neurofilaments, the
major class of intermediate filaments in neurons, in contrast to the devastating
effects of microtubule disruption (above). All three neurofilament subunits can
be deleted without loss of axonal viability, although axonal caliber decreases
without NF-M or NF-L (Elder
et al.
, 1994; Loewen
et al.
, 1997, 1998). Deletion of
the peripheral nerve intermediate filament protein peripherin also affects only a
small subset of the axons that express it (Lariviere
et al.
, 1998; Zhu
et al.
, 2002).
Several proteins not required for axon survival are mutated in neurode-
generative diseases. App, tau,
et al.
-synuclein, and ataxin 3 are mutated in some
hereditary forms of Alzheimer's disease, frontotemporal dementia, Parkinson's
