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In-Depth Information
example, the Rho GTPase
miro
confers calcium sensitivity on mitochondrial
transport (Guo
, 2005; Wang and Schwarz, 2009). Under normal circum-
stances, this causes mitochondria to accumulate in regions of high calcium influx
such as synapses where ATP synthesis and calcium sequestration are important
(Macaskill
et al.
, 2009). Another consequence, however, is that mitochondrial
movements stall with excessive calcium influx, as in excitotoxicity (Rintoul
et al.
et al.
, 2003). Continued movement of other cargoes in high calcium conditions
shows the specificity of this effect (Brady
, 1984). NGF and Tnf also cause
mitochondria to pause, probably acting through PI3 kinase and Jnk signaling
pathways, respectively (Chada and Hollenbeck, 2004; Stagi
et al.
, 2006). NGF
seems to preferentially affect anterograde transport and not stall other cargoes,
whereas TNF disrupts mitochondrial transport in both directions along with
synaptophysin transport. Finally, some proteins such as Gap43 are anchored to
vesicle membranes by palmitoylation (El-Husseini
et al.
, 2001). This process is
essential for their axonal targeting but likely has little effect on proteins that use
other mechanisms.
et al.
F. Traffic congestion: Partial blockages and axonal swellings
Limited disruption of transport can take an entirely different form. Instead of a
few specific cargoes being severely disrupted, the flow of many cargoes can be
partially restricted. Organelle-filled swellings in kinesin or dynein-deficient
Drosophila
appear as “traffic jams,” but mitochondria continue to move into
and out just as a queue on the motorway has cars leaving at one end and joining
at the other (Pilling
causes similar
axonal swellings, but live imaging shows that microtubule whorls within them
continue to support transport (Shemesh
et al.
, 2006). Overexpression of tau in
Aplysia
, 2008; Fig. 5.2). Only a fraction of
cargoes become trapped. The same may be true in mammals. Axonal swellings
near amyloid plaques in a mouse Alzheimer's disease model grow to the size of
neuronal cell bodies and are packed with short, rounded mitochondria and
markers of poor axonal transport (Fig. 5.2). Remarkably, however, more distal
axon regions survive many months without degenerating, indicating that enough
material flows through the swellings to support distal axons (Adalbert
et al.
et al.
,
2009).
G. Reduced traffic flow: Ageing and decline
Axonal transport falls dramatically with ageing, affecting fast and slow transport
of many cargoes both in retrograde and anterograde directions (Castel
et al.
,
1994; Fernandez and Hodges-Savola, 1994; Frolkis
et al.
, 1997; Li
et al.
, 2004;
McQuarrie
, 1989; Tashiro and Komiya, 1994; Viancour and Kreiter, 1993).
In rats aged two years, the average velocity of axonal transport is less than half
et al.
