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that the paradoxical partial rescue of SOD1
G93A
transgenic mice by a mutation
affecting retrograde transport could reflect a rebalancing of anterograde and
retrograde transport (Kieran
, 2005). Molecular switches regulating the
direction of axonal transport (Colin
et al.
, 2003) provide
further scope for directional imbalances when they go wrong, but could also be
targets for strategies to restore the balance.
et al.
, 2008; De Vos
et al.
D. Banned from driving: Cargo-specific defects
Cargoes travelling in the same direction can be affected to different extents. Viral
overexpression of A53T alpha-synuclein in rat substantia nigra to model Parkin-
son's disease significantly decreases how much Kif1A, Kif1B, Kif2A, and Kif3A
reach the striatum after 8 weeks, while Kif5 is barely changed (Chung
,2009).
Conversely, mutation of Kif5a alone is sufficient to cause juvenile onset hereditary
spastic paraplegia (SPG10) (Reid
et al.
kinesin 3
family protein specifically blocks transport of synaptic vesicle precursors without
altering mitochondria and other cargoes (Pack-Chung
et al.
,2002). Mutation of a
Drosophila
,2007). Overexpres-
sion of K369I human tau in mice causes a large reduction in the amount of tyrosine
hydroxylase, App, Gap43, and some other cargoes in the striatum, but no change
in synaptophysin and synaptotagmin (Ittner
et al.
,2008). The motor proteins,
Kif5B, Klc, and Kif1A, are also differentially affected. Finally, a mutant form of
Huntingtin carrying an expanded polyglutamine repeat slows Bdnf transport but
not that of mitochondria (Gauthier
et al.
,2004).
Specific axonal transport defects can also result from alterations to
scaffold proteins linking motor proteins to their cargoes. Mutation or overexpres-
sion of one scaffold protein, the
et al.
Jip-1 homolog Aplip-1, perturbs
anterograde transport of synaptobrevin-tagged vesicles but not of mitochondria,
and causes axonal swellings and larval paralysis (Horiuchi
Drosophila
et al.
, 2005). Another
scaffold protein,
, is critical for the anterograde axonal transport of mito-
chondria, but its loss leaves synaptic vesicles unaffected (Glater
milton
et al.
, 2006;
Stowers
, 2002).
Thus, disruption of microtubules affects all traffic by closing the road,
while changes to the motors and regulators of axonal transport often stop only
some “vehicles.” An intriguing prospect is that different disorders may result
from failure to transport different cargoes.
et al.
E. Faulty signals
It is not enough for axonal transport to deliver cargoes to axons. They must also
be deposited in the correct location or risk ending up centimeters away from
where they are needed. The signaling pathways controlling this are starting to
become clear and provide further scope for axonal transport to go wrong. For
