Biology Reference
In-Depth Information
disease, and spinal cerebellar ataxia, respectively. Furthermore, Bace and PS1 are
responsible for cleaving the pathogenic A
1-42 species from its precursor App as
a key step in Alzheimer's disease pathogenesis. Considering the major role of
synapse loss played in many of these diseases, the ability of axons and synapses to
survive without these proteins suggests that gain-of-toxic-function mechanisms
(e.g., protein aggregation) are most likely to underlie their roles in disease.
Alternatively, mice could be too short-lived, or their axons too short, to model
the degenerative stages of the human disease in some cases.
Perhaps most remarkably of all, second instar larvae with the
Drosophila
mutation
have axons that survive up to 5 days without mitochondria.
Milton is a scaffold protein essential for anterograde axonal transport of mito-
chondria, but without it, axons develop and retain a normal ultrastructure and
continue to transport other components, including synaptic vesicles (Glater
et al.
milton
, also has a severe
depletion of axonal mitochondria but retains basal neurotransmitter release
(Guo
, 2006; Stowers
et al.
, 2002). Another mutant,
miro
, 2005). The larvae reach the third instar, extending axons as long
as 1.5 mm (Tom Schwarz, personal communication). A possible explanation for
how these axons generate enough ATP to survive comes from SCG primary
culture studies, which show that glycolysis makes a significant contribution to
axonal ATP synthesis (Tolkovsky and Suidan, 1987; Wakade
et al.
, 1985).
Together, these observations support the concept that axon survival
depends much more on some cargoes than others, and Tables 5.1 and 5.2 begin to
highlight which proteins are fundamentally important for axons to survive and
which are dispensable.
et al.
V. PROTEIN TURNOVER FAST AND SLOW
Of course, the response of axons to long-term absence of proteins only partially
models the deficiency caused by blocking axonal transport. For example, an acute
block of axonal transport (e.g., by injury, ischemia, or toxins) impairs delivery of
new cargo, but molecules or organelles already present in axons may be unaffected.
Thus, even if their function is essential for axon survival (Table 5.1), the effect may
not be felt until the axonal pool turns over. The effects of chronic transport
impairment (e.g., in ageing, amyloid or other axonal swelling pathology
(Fig. 5.2), or faulty axon-glia interactions) may also depend on half-life. This is
because short-lived cargoes are less likely to reach distal axons than long-lived ones
if the journey takes too long. Thus, a possible basis for “dying back” disorders
(Cavanagh, 1979) is a delay in axonal transport of proteins that are both short-
lived and essential for axons, depriving distal axons of the replenishment they
constantly need.
