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Axonal transport and neurodegenerative

disease: vesicle-motor complex formation
and their regulation
This article was published in the following Dove Press journal:
Degenerative Neurological and Neuromuscular Disease
10 March 2014
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Eric N Anderson* Abstract: The process of axonal transport serves to move components over very long distances
Joseph A White II* on microtubule tracks in order to maintain neuronal viability. Molecular motors – kinesin and
Shermali Gunawardena dynein – are essential for the movement of neuronal cargoes along these tracks; defects in this
pathway have been implicated in the initiation or progression of some neurodegenerative diseases,
Department of Biological Sciences,
The State University of New York at suggesting that this process may be a key contributor in neuronal dysfunction. Recent work
Buffalo, Buffalo, NY, USA has led to the identification of some of the motor-cargo complexes, adaptor proteins, and their
*These authors contributed equally regulatory elements in the context of disease proteins. In this review, we focus on the assembly
to this work of the amyloid precursor protein, huntingtin, mitochondria, and the RNA-motor complexes
and discuss how these may be regulated during long-distance transport in the context of neuro-
degenerative disease. As knowledge of these motor-cargo complexes and their involvement in
axonal transport expands, insight into how defects in this pathway contribute to the development
of neurodegenerative diseases becomes evident. Therefore, a better understanding of how this
pathway normally functions has important implications for early diagnosis and treatment of
diseases before the onset of disease pathology or behavior.
Keywords: kinesin, dynein, amyloid precursor protein, huntingtin, microtubules

Introduction
Axonal transport within neurons is essential for cell viability, supplying the synapse
with important components for survival. Unlike other cell types, neurons are polarized
and can extend long distances (up to 1 m in humans). Many proteins that are newly
made in the cell body are actively transported down axons along microtubule tracks
by molecular motors. Microtubules (MTs) are long, hollow cylinders approximately
25 nm in diameter that are comprised of α- and β-tubulin dimers.1 Therefore, all of the
transported components synthesized in the cell body must be assembled, associated
within complexes, attached to a particular engine or motor, and efficiently transported
down the axon. As such, all of these steps must be highly regulated and any misregula-
tion could result in transport deficits leading to neuronal dysfunction.
Experiments on transport kinetics classified two types of axonal transport, as fast
and slow.2 Fast axonal transport moves components at rates of 100–400 mm day−1
Correspondence: Shermali Gunawardena (1–5 µms−1), while slow transport moves components considerably slower, 0.2–5 mm
The State University of New York at
Buffalo, 109 Cooke Hall, North/Amherst day−1 (0.01–0.001 µms−1). Fast axonal transport primarily transports vesicular cargoes
Campus Buffalo, NY 14260, USA and membrane-bound organelles, while slow axonal transport transports cytoskeletal
Tel +1 716 645 4915
Fax +1 716 645 2975
components. Current knowledge indicates that the same molecular motors mediate
Email [email protected] both fast and slow axonal transport.3–5

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In this review, we focus on fast axonal transport and its

motor-cargo complexes. Given the complexity of axonal Vesicle
transport machinery, deficits in axonal transport can occur by
several means, including complications with motor function, KLC
problems with cargo complex assembly or cargo attachment Anterograde

to motors, as well as malfunctions in regulatory elements. Kinesin-1

Recent studies have shown that deficits in these processes
KHC
can either cause or exacerbate neurodegeneration.6,7 Some
− +
proteins involved in neurodegenerative diseases have also Microtubule
been implicated in this pathway with human disease muta- Retrograde
p150Glued Dynein
tions in these proteins causing defects in axonal transport.8–12 Dynactin
Importantly, mutations in motor proteins have also been p50
reported to cause neurodegeneration.13 Furthermore, many
of these disease proteins normally form complexes that Vesicle

have functional roles in axonal transport. Alterations in the

assembly or defects in the regulation of these protein com- Figure 1 Conventional kinesin (kinesin-1) and cytoplasmic dynein motor complex
plexes may result in transport deficits instigating the disease on a MT for axonal transport.
Notes: Kinesin-1 through the KHC head motor domains binds MTs. Vesicles associate
pathology and behavioral defects seen in disease states. Thus, with kinesin-1 via associations with the KLC or via adaptor scaffolding proteins. Cargo
elucidating the mechanisms of axonal transport has important complexes attached to kinesin-1 are transported anterogradely (toward + end of
MTs; arrow). Cytoplasmic dynein associates with dynactin for retrograde movement.
implications for potential early diagnosis of neuronal disease Dynactin consists of multiple proteins, but only p150Glued and p50 are shown for
simplicity. Dynein interacts with dynactin via associations between p150Glued and
and for the development of therapeutic interventions before DIC subunits. Dynein binds MTs via the tip of the stalk of DHC, while dynactin also
the onset of neuronal death. associates with MTs via the N-terminal globular domain of p150Glued. Dynein–
dynactin motor complex transports cargoes retrogradely (toward - end of the MTs;

Motor proteins and regulatory arrow).

Abbreviations: KHC, kinesin heavy chain; MTs, microtubules; KLC, kinesin light chain;
models DHC, dynein heavy chain; DIC, dynein intermediate chain; DLC, dynein light chain.

Conventional kinesin motor

The kinesin-1 motor protein, also called “conventional dimerize, and the C-terminal tail domain interacts with the
kinesin”, is part of a subfamily of motor proteins associated kinesin light chain (KLC) subunit.22,25–29 Classical studies
with MTs and move toward their plus ends (Figure 1).14 An using truncated fragments of Drosophila KHC expressed
important feature of kinesin-1 is its ability to take 8 nm in Escherichia coli revealed that KHC is able to exclusively
steps as measured using in vitro experiments, performing induce movement along MTs.30 Fragments that specifically
processive movement.15 Kinesin-1 was first identified in contained the motor domain were capable of inducing MT
squid axoplasm16,17 and is highly conserved in many spe- motility,30 indicating that the KHC motor domain is required
cies.18–22 Biochemical analyses of kinesin-1 from bovine for movement.
brains revealed that it is a tetramer consisting of two heavy Loss of function of KHC in Drosophila showed larval
chains (120 kd) and two light chains (62 kd).23,24 paralysis and axonal accumulations of synaptic vesicles in
In invertebrates, such as Drosophila, a single gene is larval segmental nerves with lethality at early third instar
responsible for each subunit while, in mammals, kinesin-1 larval stages.31–34 In mice, KIF5B is expressed ubiquitously
is more complex and requires three genes for kinesin heavy while KIF5A and KIF5C are neuronal specific. Targeted
chains (KIF5A, KIF5B, KIF5C) and three for kinesin light disruption of the KIF5B or KIF5A gene in mice caused
chains (KLC1, KLC2, KLC3).20,21 embryonic lethality,35,36 while knockout of the KIF5C gene
Sequence analysis, expression studies,22 and electron caused a reduction in brain size with no gross changes in
microscopy25,26 revealed that the kinesin heavy chain (KHC) the nervous system. These mice were viable.37 Primary cul-
subunit contains three domains: a motor domain; a stalk tures from KIF5B null embryonic cells exhibited striking
domain; and a tail domain. The globular motor domain at phenotypes of mitochondrial and lysosomal distribution,
the N-terminus of KHC contains sites for MT and adenos- indicating that KIF5B may be essential for mitochondrial
ine triphosphate (ATP) binding. The α-helical coiled-coil and lysosomal dispersion.35 A postnatal knockout of KIF5A
stalk domain contains sites where two heavy chains can exhibited seizures and death at approximately 3 weeks of age

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Dovepress Axonal transport and diseases

with neurofilament proteins accumulating in the cell bodies KLC was found to associate with Alzheimer’s disease
of peripheral sensory neurons, accompanied by a reduction (AD),49 indicating that mutations in KLC may also lead to
in sensory axon caliber.36 Older animals also developed age- neuronal dysfunction.
dependent sensory neuron degeneration, accumulation of
neurofilaments in cell bodies, reductions in axons, and hind Cytoplasmic dynein motor
limb paralysis. Recent studies indicated that KIF5A is also Dynein, the retrograde motor, (Figure 1), is a multisubunit
essential for gamma-aminobutyric acid receptor transport complex that consists of two catalytic heavy chains (DHC),
and that deletion of KIF5A caused epileptic phenotypes.38 two intermediate chains (DIC), and several light chains
Interestingly, a missense mutation in the mammalian KIF5A (DLC: Tctex1; roadblock; and LC8 subfamilies).14,50,51 In
gene was identified in a family with hereditary spastic mammals, DHC is encoded by a single gene (Dync1h1),
paraplegia, an inherited neurodegenerative disease charac- DIC is encoded by two genes (Dync1i1, Dync1i2), and DLC
terized by lower limb spasticity and weakness.39 Thus far, is encoded by a family of three genes (Dynlt1, Dynlt3, Dyn-
19 of the 21 hereditary spastic paraplegia (SPG) disease lrb1, Dynlrb2, Dynll1, Dynll2).51,52 The motor domain is
mutations identified in humans are localized to the motor localized in the C-terminal region of DHC.53,54 Structurally,
domain of KIF5A,39,40 indicating that these mutations cause the C-terminus of DHC is comprised of six tandemly linked
disease by perturbing the proper transport of components to AAA (ATPases Associated with diverse cellular Activities)
the synapse. Indeed, the hereditary spastic paraplegia muta- domains,53–56 with the first four AAA domains essential for
tion N256S, which occurs within the KIF5A gene, severely dynein movement.57,58 Force production and translocation
disrupted MT-based transport in Drosophila.13 Furthermore, are achieved through the N-terminal region of DHC, also
a KIF5A mutation was also detected in a Charcot–Marie– known as the “stem domain.”59 In vitro studies of the stem
Tooth type 2 patient belonging to a SPG mutant family.40 domain in Dictyostelium revealed that the dimerization of
Thus, mutations in KHC can lead to neurodegeneration due DHC and the binding of DIC and DLC can be achieved
to deficits in axonal transport. through this region.60 Collectively, the association of the
The KLC subunit contains three domains: an N-terminal smaller dynein subunits with the N-terminal region (tail
coiled-coil domain or heptad repeats which bind KHC; domain) of DHC forms the cargo-binding complex for
a tetratricopeptide repeat (TPR) domain; and a C-terminal retrograde motility.
domain. The TPR and C-terminal domains bind cargo and Cytoplasmic dynein associates with a protein complex
function as a linker between KHC and the transported called dynactin (Figure 1) for retrograde motility. Dynactin
­cargoes.41 The TPR domain, which is a protein–protein is composed of: p150Glued; dynamitin (p50); p62; actin-
interaction domain, has been shown to interact with a variety interacting protein (Arp)1 and Arp11; actin; p24; p25; p27;
of adaptor proteins, such as the JNK-interacting proteins and capZ α and β;61 and plays an important role in dynein’s
(JIP), huntingtin (HTT)-associated protein (HAP) 1,42,43 ability to bind to vesicles.61,62 Dynactin also binds to MTs
and amyloid precursor protein (APP).44 Structurally, TPR via p150Glued,63,64 the largest subunit that interacts with
is composed of tandem repeats of 34 amino acids that each both MTs and dynein. The N-terminal of p150Glued binds
form a helix-turn-helix arrangement and a superhelical MTs while the two coiled-coil regions are required for its
conformation of multiple TPR repeats. 45 While Droso- dimerization and interaction with DIC.63,65,66 Mutations in the
phila has only one KLC gene, mammals have three KLC MT-binding domain of p150Glued showed decreased affinity
genes – KLC1, KLC2, and KLC3. KLC1 is predominantly for MTs resulting in neuronal abnormalities.67 Binding of
expressed in neuronal tissues while KLC2 shows a more the dynein–dynactin complex to vesicles is mediated by the
ubiquitous pattern of expression.46 Removal of functional Arp1 filament, which has been shown to bind to the spectrin
KLC1 resulted in significantly smaller mutant mice that matrix on organelles.68–71
exhibited pronounced motor disabilities. 45 KLC2 was Both dynein and dynactin are required for viability. Using
shown to play a role in Na/K-ATPase-containing vesicles in targeted disruption mice homozygous for loss of DHC died
alveolar epithelial cells.47 Interestingly, KLC3 appears to early, while heterozygous mice showed no abnormalities.72
play a unique and specialized role in spermatids.48 Loss However, in vitro cultures of DHC–/– blastocysts showed
of function of the single KLC gene in Drosophila showed defects in Golgi vesiculation and lysosome dispersion,
paralysis phenotypes, axonal accumulations, and a third ­suggesting that DHC is required for cell proliferation and
instar larval lethality.34 Interestingly, a polymorphism in proper distribution of endosomes and lysosomes.73

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In flies, dynein was also essential for survival. Loss of dendrites.91 However, recent in vivo evidence has shown that
function of DHC or DLC caused lethality while partial loss there are, in fact, stable populations of both kinesin-1 and
of function mutations caused pleiotropic morphogenetic dynein motors on APP vesicles,92 suggesting that this model
defects in bristle and wing development and resulted in female is incorrect, at least for APP vesicles under physiological
sterility.74–76 Most of these defects were associated with loss conditions. Furthermore, in retrogradely moving early endo-
of cellular shape and structure due to a disorganization of somes in Ustilago maydis, dynein-containing vesicles also
the cytoskeleton.75 Functions for DLC in the ­regulation of contained the kinesin-3 complex, while kinesin-3 was located
axonogenesis have also been shown, indicating a role of cel- on vesicles moving in both directions.93 Therefore, although
lular motors in growth cone guidance.77 Interestingly, ­missense more than one type of kinesin together with dynein could be
point mutations in DHC resulted in decreased retrograde associated with cargo during motility under physiological
transport and progressive motor neuron degeneration accom- conditions, only one motor might be active at a given time.
panied by the formation of Lewy-like inclusion bodies.7 Two The tug-of-war model suggests that both kinesin-1 and
of these missense point mutations, legs at odd angles (Loa) dynein motors are simultaneously active on vesicles and that the
and cramping 1 (Cra1) occurred in the DIC binding site and motors producing the highest net force ultimately move vesicles
in the homo dimerization site of DHC. in their respective direction,94 similar to a tug-of-war, with back-
Mutations in p150Glued are also linked to neurodegen- and-forth motility, ultimately resulting in the net movement
eration. Mutations in the p150Glued dynactin subunit were in one direction. Much of the evidence for this model comes
identified in familiar forms of motor neuron disease, includ- from studies done in vitro using purified motors. In contrast,
ing amyotrophic lateral sclerosis (ALS) and distal spinal and the coordination model of bidirectional motility proposes that
bulbar muscular atrophy.78–83 A mutation in p150Glued was opposite-polarity motors work in regulated concert to achieve
also identified in Perry syndrome, a rare atypical form of the observed complex vesicle motility rather than a simple tug-
Parkinson’s disease resistant to L-3,4-dihydroxyphenylala- of-war mechanism. In this context, at one particular time, one
nine (L-DOPA).84 Interestingly, postnatal overexpression of motor is active for movement while the other motor is inactive.
the p50 dynactin subunit induced late onset motor neuron While the active motor dictates net movement in one direction,
disease in mice.78 Motor nerves from specimens obtained there is little back-and-forth motility.
from ALS patients showed decreased transport of organ- Part of the reasoning behind the tug-of-war model lies
elles, such as mitochondria.85 Interestingly, in vivo studies in the observation that many transported vesicles will often
in intact sciatic nerves from the G93A superoxide dismutase change directions quickly in a process called “reversing”.95
1 (SOD1) transgenic ALS mouse model showed decreased In 2009, Soppina et al96 using Dictyostelium cells showed
retrograde transport, which preceded visible disease symp- that endosomes experience elongation and slowed velocities
toms.86,87 Collectively, these observations indicate that during reversals, which is consistent with a tug-of-war mecha-
defects in dynein/dynactin function can lead to progressive nism. However, these results do not preclude the possibility
neurodegeneration. of a transient tug-of-war mechanism that could result from
delayed inactivation of externally regulated motors. Several
Regulatory models studies have used various mathematical models, such as
of bidirectional movement Monte Carlo simulations and models based on a lipid drop-
Since both kinesin-1 and dynein motors are found together on let system97,98 to show that the tug-of-war model is not only
mobile vesicles,88,89 experimental emphasis has been placed cooperative, but it can also be used to explain the dynamics
on elucidating the mechanisms of how these motors coordi- of bidirectional movement, such as reversing.97,98
nate to achieve bidirectional motility.90 Thus far, three models Research using origami DNA99 showed that opposite-
have been proposed to explain bidirectional transport – the polarity motors work to stall synthetic DNA cargoes and
exclusionary, the tug-of-war, and the coordination models. seem to follow a cooperative tug-of-war model. ­Furthermore,
The exclusionary model of transport suggests that there is the motility of purified vesicles reconstituted in vitro closely
only one type of motor or motor complex attached to a vesicle resembled the movement of LysoTracker-positive vesicles
at a given time, and so these vesicles move unidirectionally. in primary neurons, where bidirectional motility was inter-
In this model, different motors would have to bind/unbind to rupted with frequent directional switches, diffusional move-
achieve the bidirectional movement seen with many cargoes. ment, and pauses. Quantitative analysis indicated that these
Alternatively, the entire complex could hop onto opposite vesicles copurified with a low number of stably bound motors,
polarity MTs in areas where MTs are not unipolar, such as ­suggesting that a small complement of tightly bound motors,

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Dovepress Axonal transport and diseases

and small changes in the number of engaged motors can dynein motors with motors of similar polarity (such as Unc-
mediate large changes in the motility of cargo. These observa- 104 for kinesin-1) was able to activate cargo movement in the
tions are consistent with predictions for a motor coordination opposite direction.104 ­However, mutated motors with active
via a stochastic tug-of-war model, where transport could be heads but lacking motility failed to initiate retrograde trans-
driven by the force-dependent kinetics of opposing motors port. As a result, it was suggested that the opposing force
in the absence of external regulation.100 generated by the anterograde motor could activate retrograde
Recently, many researchers have leaned toward a motor movement. Furthermore, a complete and stable kinesin-1
coordination model with motor regulation to explain bidirec- holenzyme not only mediated anterograde movement of
tional motility in vivo. This is, in part, due to the relatively prion protein-containing vesicles, but it also activated its
high velocities of vesicle motility observed during in vivo retrograde movement.105
analysis, which contradicts with the in vitro velocities. Since Together, these studies indicate an interdependence of
bidirectional motility must occur in a crowded environ- opposite-polarity motors on their activation and motor func-
ment, many cargoes must maneuver in both directions on a tion and suggest that precise regulation is needed to maintain
single microtubule track. In vivo studies of peroxisomes in complex motility in axons. Perhaps activation of both kine-
Drosophila S2 cells indicated that peroxisomes can move sin-1 and dynein/dynactin via phosphorylation may be an
at very fast velocities, reaching speeds much faster than important mechanism by which coordination of these motors
those observed during in vitro experiments that contained occur under physiological conditions.108,208 Indeed, both KHC
only one type of motor polarity (ie, [+] ended motors, such and KLC subunits are known to be phosphorylated and con-
as kinesin-1).101 In vivo analysis of APP vesicles in Droso- tain sites for several kinases.245,256 While little is known about
phila larvae showed that APP velocities were dependent on dynein phosphorylation, putative phosphorylation sequences
the amount of kinesin available, as 50% reduction of KHC are seen in dynein subunits.208 While binding of dynactin to
resulted in decreased velocities.92 dynein activates retrograde motility,106,107 evidence also sug-
Reduction of dynein affected both anterograde and gests that kinesin-1 can mechanically interact with dynein to
retrograde velocities,92,128 indicating that the functions of coordinate motor activity and movement.88,92,105,128 Therefore,
kinesin-1 and dynein are interdependent and that loss of several mechanisms of motor regulation and coordination
either motor can lead to the impairment of bidirectional must exist in vivo for proper bidirectional motility of several
transport. Indeed, several studies support this proposal. cargos on a single microtubule track.
Barkus et al showed that mutations in Drosophila Unc-104,
a kinesin-3 protein, also inhibited retrograde movement.102 Motor-cargo complexes
Likewise, in axonal neurofilaments, knockouts of kinesin-1 in neurodegenerative disease
in mice and reductions of dynein motors inhibited both Recent work suggests that several motor-cargo complexes
anterograde and retrograde transport.103 Pilling et al showed are transported on a single microtubule track. Several of
that mitochondria are not only transported by kinesin-1, these motor-cargo complexes contain proteins involved in
but that kinesin-1 mutants drastically reduced retrograde neurodegenerative disease (Table 1). Here we will discuss a
transport.89 ­Furthermore, replacement of either kinesin-1 or few of these motor-cargo complexes with an emphasis on the

Table 1 Vesicle-motor complexes associated with neurodegen­erative diseases

Cargo/vesicle Motor protein Complex components Disease References
complex involved
APP KHC, KLC, dynein PS1, GAP-43, BACE, Alzheimer’s 36, 98, 100, 101,
TrKA, synapsin, JIP1, JIP3 disease 102, 119
HTT KIF5, KLC, dynein HAP1, HAP40, GAPDH Huntington’s 35, 124, 127, 128,
Rab11, BDNF disease 129, 190, 218, 219
Mitochondria KIF5, KIF1B-alpha, Milton–Miro complex, Parkinson’s 138, 142, 145–148,
dynein JIP1, RanB2, pink-parkin, disease, CMT2A 157, 208, 209
Mfn2, syntabulin
mRNA–protein KIF5, dynein FMRP, La mRNA Fragile X 165, 172, 175
complex syndrome
Abbreviations: APP, amyloid precursor protein; HTT, huntingtin; KHC, kinesin heavy chain; KLC, kinesin light chain; PS1, presenilin 1; GAP43, growth-associated protein 43;
BACE, beta-site amyloid precursor protein cleaving enzyme; TrKA, tyrosine kinase receptor type A; JIP1, c-Jun-amino-terminal kinase-interacting protein 1; JIP3, c-Jun-amino-
terminal kinase-interacting protein 3; HAP1, huntingtin-associated protein 1; HAP40, huntingtin-associated protein 40; GAPDH, glyceraldehyde 3-phosphate dehydrogenase;
BDNF, brain-derived neurotrophic factor; Mfn, mitofusin; CMT, Charcot–Marie–Tooth; FMRP, Fragile X mental retardation protein.

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normal function of these disease proteins to determine how A B

defects in vesicle motility result in neuronal dysfunction. APP
P vesicle
AP icle APP APP
s
ve vesicle vesicle JNK

APP-cargo complex P(T668)

AP
P

AP
P(S421)

P1

P
JI
APP, the AD protein, is found in many tissues, but it is highly
enriched in the brain.109,110 Although the function of APP
− + − +
remains unclear, there is evidence that it can function as a Microtubule

C
receptor for kinesin-1 during axonal transport. While APP APP
APP PS1
vesicle
can bind to components of the extracellular matrix, the struc- vesicle

tural and sequence analysis of APP gives insight into several BACE
γ-cleavage

possible functional domains, including domains for protease

inhibition.111 Further, APP can function as an extracellular
receptor112,113 much like Notch because of its similarity in struc- − +

ture and the ability of proteases, such as secretases, to cleave

full-length APP into fragments. Similarly, APP has also been D APP
PS1 PS1 vesicle PS1
APP APP APP
implicated in cell adhesion through the binding of extracellular vesicle
P
vesicle
P
−esicle
P

K3β

K3β
K3β
matrix proteins.114,115 There is also evidence for APP to function

GS

GS
GS
as a regulator of neuronal outgrowth and aptogenesis during P P

differentiation116–118 and neuronal repair following trauma.119 Anterograde

Concurrent with roles in neurite growth and synaptogen- −

P P +

esis, APP is transported by fast axonal transport via KLC,

either directly since the C-terminus of APP has been found Figure 2 Models of APP-cargo complexes and their regulation during transport.
Notes: (A) APP can associate with kinesin-1 in two ways. APP associates with
to bind to KLC120–122 or indirectly via an interaction between kinesin-1 via interactions with JIP1. This interaction may require APP to be
KLC and JNK interacting protein 1 (JIP1).121,247 Biophysical phosphorylated at T668. Alternatively, the C-terminus of APP can associate with
kinesin-1 via KLC through its TPR domains. (B) JNK phosphorylation of JIP1 at
evidence indicated that 15aa of the C-terminus of APP was S421 regulates APP association with kinesin-1 and dynein. Phosphorylation of JIP1
sufficient to promote the transport of APP in squid axons122 is thought to promote anterograde transport, while dephosphorylation promotes
retrograde transport. Arrows indicate direction of motility. (C) APP is in a vesicular
and that APP beads had a high-binding affinity for kine- compartment that contains BACE, PS1, GAP43, synapsin, and TrkA. PS1 is the
sin-1.123 In addition, genetic evidence showed that excess catalytic component of gamma (γ) secretase that is known to cleave (scissor) APP
and may serve to release APP vesicles from motors. (D) PS1 contains two putative
human APP or Drosophila APP-like (APPL) and the loss of glycogen synthase kinase 3-beta (GSK-3β) phosphorylation sites in its loop region.
Phosphorylated PS1 may serve as a scaffold for GSK-3β to associate with PS1 similar
function of Drosophila APPL resulted in phenotypes similar to the β-catenin-PS interaction, thus enabling GSK-3β to phosphorylate kinesin,
to motor protein mutants, indicating a function for APP in which may release the vesicle from kinesin-1 or regulate motility of APP vesicles.
It remains unclear whether these events are specific to APP vesicles or are general
axonal transport.124 to all vesicles.
Interestingly, the C-terminal deletions of human APP or Abbreviations: APP, amyloidal precursor protein; T668, threonine 668; S421,
serine 421; JIP1, Jun N kinase interacting protein 1; KLC, kinesin light chain; TPR,
APPL (including the kinesin-binding region) disrupted APP tetratricopeptide repeat; JNK, Jun N kinase; BACE, beta-site amyloid precursor
transport and failed to interact functionally with kinesin-1.124 protein cleaving enzyme; PS1, presenilin; GAP43, growth-associated protein 43;
TrkA, tyrosine kinase receptor type A.
JIP1 has also been shown to interact preferentially with APP
that is phosphorylated at threonine 668 (Thr668) and affects p­ resenilin 1 (PS1), the catalytic component of γ-secretase);
the transport of phosphorylated (p)APP vesicles125 (Figure 2A). ­beta-site APP cleaving enzyme 1 (BACE1); synapsin 1;
Recently, subpixel colocalization analysis suggested that APP tyrosine kinase receptor type A (Trk A); and growth-­associated
vesicles contain both kinesin-1 and dynein,126 indicating that protein 43 (GAP43).120 In addition, APP functionally interacts
APP utilizes both kinesin-1 and dynein motors for bidirec- with PS1, BACE1, KLC, and c-Jun-amino-terminal kinase-
tional motility within axons. Furthermore, studies have also interacting protein 1 (JIP1),125,128–130 and some of these pro-
shown that the aberrant processing of APP by either β or γ teins have also been shown to have enzymatic activity on APP
secretase/presenilin can lead to the impaired transport of APP itself, illustrating the importance of APP as an axonal protein.
along axons which, in turn, may alter its normal function, Evidence that APP is not transported in vesicles containing
leading to synaptic degeneration.127,128 synaptotagmin120,128 further solidifies APP as a marker for a
During axonal transport, APP is thought to be contained distinct subset of fast axonal transport vesicles. APP has also
within a subclass of vesicles that contain the proteins: been shown to be cotransported with calsyntenin-1, which

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is a ligand for KLC.131 Further, reduction of ­calsyntenin-1 has also shown that GSK-3β-mediated activities on APP may
impaired APP transport and caused accumulations of Aβ,131 be via an action on presenilin,128,208 which is found on APP-
perhaps due to the fact that BACE1 and PS1 form a complex containing vesicles129 and is known to cleave APP.139,140 In vivo
with APP.129 Although a study using fluorescent imaging imaging showed that presenilin also negatively regulates APP
failed to find colocalization of APP and BACE1 in retinal motility, similar to GSK-3β.128 Loss-of-function presenilin
ganglion cells,132 BACE1 activity has also been observed mutants resulted in increased APP vesicle velocities in both
in axons.132 While enhanced β-secretase processing altered the anterograde and retrograde directions along MTs.128 In
APP axonal transport,127 a recent study showed that BACE1 contrast to cell culture data, in vivo analysis showed that pre-
and APP vesicles converge via an endocytosis dependent senilin can increase the activity of GSK-3β, which may lead
pathway in neurons.133 In cultured hippocampal neurons, to increased kinesin-1 and dynein binding to APP vesicles,
dendritic APP/BACE1-containing vesicles were largely causing uncoordinated motility.208 Perhaps PS1 and GSK-3β
segregated in physiologic states, where BACE1 was sorted may form a complex with motors to regulate motility in
into acidic recycling endosomes, and APP was conveyed in vivo. Indeed, PS1 associates with GSK-3β141 and can act as
­Golgi-derived vesicles. However, upon activity induction, a a potential scaffold to bring GSK-3β within close proximity
known trigger of the amyloidogenic pathway, APP was routed of β-catenin (Figure 2D). Similarly, perhaps PS1 can also
into BACE1-positive recycling endosomes via a clathrin- act as a scaffold that brings GSK-3β into close proximity of
dependent mechanism,133 suggesting that BACE1 and APP kinesin-1 and dynein, thereby regulating the motility of APP
can be together in a particular functional pathway. vesicles. Alternatively, since PS1 is the catalytic component
Recent work has demonstrated that APP vesicle motil- of the gamma secretase complex, perhaps PS1 may cleave
ity is regulated through several different mechanisms. APP vesicles from motors139,140 (Figure 2C) and may serve as
­Anterograde velocities of APP vesicles are dependent on another form of regulation of APP motility. Indeed, high lev-
kinesin-1 concentration, and DIC may play a role in the coor- els of APP peptides were shown to impair transport in squid
dinated regulation of APP motility.92 APP is phosphorylated axons,122 which may be a mechanism of disrupting transport
and, although the role of phosphorylation is still uncertain, in some forms of familial Alzheimer’s disease.
it may play a role in the regulation of APP vesicles during Since the transport of APP and its associated proteins
axonal transport. APP is phosphorylated at residue Thr668, may be regulated through several mechanisms, it is not
although it is unclear which kinase is responsible for this surprising that misregulation of these complexes can lead to
phosphorylation. Previous studies have shown that cyclin the impairment of axonal transport, which may be an early
dependent kinase (CDK5), and c-Jun amino-terminal kinase trigger in disease pathology. Indeed, axonopathy and transport
(JNK), are potential kinases responsible for APP phospho- deficits were observed in mouse models of AD that preceded
rylation at Thr668.134,135 known disease-related pathology by more than a year and in
Further work has shown that JIP1 prefers to interact the early stages of AD in humans.142 Furthermore, in Down
with pAPP, such that reductions in JIP1 impaired transport syndrome, where an increased expression of APP is seen, in
of pAPP, but not APP.125 More recently,136 JIP1 has been the context of trisomy, abnormal transport of nerve growth
shown to potentially regulate the anterograde/retrograde factor and cholinergic neurodegeneration was observed,143
movements of APP. In vitro experiments showed that JNK and these transport defects were thought to be independent
can phosphorylate JIP1 at S421 to promote anterograde of Aβ production.144
movement and that lack of JIP1 phosphorylation caused ret- Taken together, these studies suggest that defects in
rograde movement via interactions with dynein (Figure 2B). axonal transport may be an early event in the progression
However, short interfering RNA experiments in cultured rat of AD and may result, in part, due to the misregulation of
cortical neurons showed no changes in APP transport with axonal transport.
reductions of JIP1.137
Recent in vivo experiments have shown that GSK-3β can HTT cargo complex
negatively regulate APP transport via kinesin-1 by regulating HTT, the protein involved in Huntington’s disease (HD), is
the numbers of active motors on these vesicles.138 GSK-3β is a ubiquitously expressed protein found in many cell types,
thought to phosphorylate KLC, causing vesicles to release but it is concentrated in neurons. HTT is comprised of two
from motors.108 (Figure 2C). Alternatively, GSK-3β can expanded regions of polyglutamine (polyQ) and polyproline,
phosphorylate KHC to regulate vesicle motility.208 Evidence at the N-terminus and approximately 28–36 HEAT repeat

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Anderson et al Dovepress

domain motifs,145 which likely form a superhelical structure146

that is involved in protein–protein interactions. The polyQ A BDNF Rab
vesicle
tract can expand to longer lengths of CAG repeats (normally, HA
P4
HA
P4

HTT

HTT
0 HAP1 0 HAP1

approximately 35 repeats) that tend to correspond to the

age of HD onset. X-ray crystallography of the N-terminus
+
of HTT147 has given insight into the structure of the polyQ −

region, showing various confirmations depending on the B Akt

P(S421)
BDNF
surrounding proteins that could potentially affect its binding
capabilities. In addition, the predicted structure of pathogenic
BDNF
and nonpathogenic N-terminal fragments of HTT aligned t
Ak ylatio
or
h
n
Anterograde
osp

HTT
HAP1

with this X-ray structure suggests an aggregation model for ph

− +

the pathogenesis of HD.148 pho PK

sph A
ory BDNF
Like APP, the primary function of HTT is still unclear. − +
latio
n
PKA

P(T598)
However, HTT is essential for development, since HTT
null mice are embryonic lethal and heterozygous mice
contain a myriad of defects, including cognitive deficits and
Retrograde

− +

­neurodegeneration.149 Despite the lack of clarity on function, C

HTT interacts with a variety of different proteins, including
rgo
Ca
huntingtin-interacting proteins and HAPs. These proteins Ca
rgo

P1
HA
P1
HTT

appear to have various functions, including regulation of

HA
polyQ
HTT
polyQ
JNK3
transcription, cell signaling, and cargo trafficking.150 The P

structure of HTT and the fact that HTT interacts with many P

different proteins implies that HTT may act as a scaffolding − +

protein that is essential for cellular trafficking.

Figure 3 Models of HTT-cargo complexes and their regulation during transport.
HTT has also been shown to have important functions Notes: (A) HTT may attach to BDNF or Rab protein containing vesicles and
associate with kinesin-1 and dynein via interactions with HAP1 and HAP40.
in axonal transport and is transported along MTs.151 Both
(B) Akt can phosphorylate HTT at S421 causing it to stabilize kinesin-1 and increase
biochemical and genetic evidence suggest that HTT interacts anterograde transport of BDNF vesicles. Dephosphorylation of HTT at S421 and
possibly phosphorylation of HAP1 by PKA may destabilize kinesin, enabling HAP1 to
directly with both kinesin9,152 and the dynein/dynactin com- associate with p150Glued and increase retrograde transport. (C) Pathogenic HTT
plex.9,153 HAP1, which binds to HTT,154,155 has also been (HTT polyQ) activates JNK3, a neuronal specific kinase, to phosphorylate KHC and
release kinesin-1 from MTs.
shown to interact with p150Glued156 and KLC.43 These Abbreviations: HTT, huntingtin; polyQ, polyglutamine; BDNF, brain-derived
findings indicate that HAP1 may act to tether HTT (and its neurotrophic factor; HAP1, huntingtin-associated protein 1; HAP40, huntingtin-
associated protein 40; S421, serine 421; PKA, protein kinase A; JNK3, Jun N kinase 3;
cargo) to the antero- and retrograde motors. Furthermore, KHC, kinesin heavy chain; MTs, microtubules.
HTT has been shown to transport vesicles containing brain-
derived neurotrophic factor (BDNF) (Figure 3A) through its perturbed with reduction of HTT,164 indicating that HTT may
interaction with both HAP1 and P150Glued.157 Interestingly, mediate the transport of Rab11 vesicles on MTs and defects
HAP1 has also recently been shown to associate with APP, in Rab11 transport may contribute to the early stages of the
since deletion of HAP1 resulted in an increased in motionless synaptic dysfunction in HD. Consistent with this proposal,
APP vesicles158 and impaired the anterograde transport of early synaptic dysfunction,165 dendritic spine loss, and neu-
APP.43 Furthermore, HTT may regulate organelle dynamics rodegeneration166 observed in HD models were reversed by
by influencing different Rab proteins (Figure 3A). Indeed, overexpression of Rab11.
Pal et al showed that HTT can mediate the transport of Much like APP, phosphorylation is also associated with
Rab5–HAP40–HTT containing early endosomes on actin the regulation of HTT. Akt has been shown to act as a molecu-
filaments.159 HTT was also linked to Rab8 through FIP2 lar switch by phosphorylating HTT at serine 421.167 This mod-
(family interacting protein 2), and this interaction regulated ification caused HTT to recruit kinesin to the BDNF vesicles,
cell polarization and morphogenesis.160 Further, impairment and possibly to dynactin, resulting in increased anterograde
of Rab11 caused the defective formation of vesicles in HD transport of BDNF vesicles in cultured cortical neurons.
models,161,162 membrane binding of Rab11 was decreased with Conversely, lack of HTT phosphorylation caused kinesin to
knockout of HD,163 and the axonal transport of Rab11 was release from MTs and to promote retrograde ­transport.168 As

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Dovepress Axonal transport and diseases

a result, perhaps pHTT may stabilize the interaction between by utilizing kinesin-1 and cytoplasmic dynein motors.89,176–179
kinesin and dynactin to promote anterograde transport. Simi- Evidence suggests that a specific protein complex is involved
larly, HAP1 is thought to be regulated via phosphorylation in anchoring mitochondria to KHC. Genetic screens in
since protein kinase A (PKA) can phosphorylate HAP1 at Drosophila identified a Rho guanosine triphosphate (GTP)
T598, causing a decrease in the association of HAP1 with ase, Miro, and trafficking protein Milton, which form a com-
dynactin and KLC.169 Interestingly, this study also showed plex for mitochondrial transport.173,177,180 (Figure 4A). While
that nerve growth factor stimulation led to an increase in Drosophila contains only one Milton gene,173,180 mammals
activated Akt and enrichment of HAP1 at neurites, indicating have two orthologs named TRAK1/OIP106/Milton1 and
an increase in HAP1 anterograde transport which is consistent GRIF1/Milton2.177 Biochemical evidence showed interactions
with Zala et al.168 Together, these findings suggest a mecha- between Miro and Milton.173,181
nism by which HTT and HAP1 work together to coordinate While the overexpression of Miro recruited Milton to
vesicle directionality through two competing kinase pathways mitochondria and regulated its trafficking in hippocampal
(PKA and Akt) (Figure 3B). neurons,181 the loss of Miro impaired the kinesin-mediated
More recently, HTT has been implicated as a scaffold transport of mitochondria.182 Evidence using yeast two-hybrid
for vesicular glycolysis machinery that regulates vesicle interaction assays, coimmunoprecipitation, and colocaliza-
transport by providing onboard energy for the transport of tion indicated that GRIF1/Milton2 directly interacts with
a subset of vesicles.170 They showed that HTT can tether KHC through its C-terminal cargo-binding domain.183 Fur-
glycolytic proteins, such as glyceraldehyde 3-phosphate thermore, the Milton interaction with KHC is independent of
dehydrogenase (GAPDH), onto BDNF vesicles,170 suggest- KLC.173 Therefore, Milton functions as an adaptor that links
ing that the HTT-mediated glycolytic machinery provides KHC to M ­ iro-mediating mitochondrial transport.
the ATP that is used by BDNF vesicles for axonal transport. Since mitochondria also undergo retrograde transport in
These observations suggest that HTT is not only important axons, a Miro complex could exist with dynein. Loss or overex-
for carrying cargoes to target regions, but that HTT is also pression of Miro in Drosophila reduced ­retrograde transport of
required for the proper transport of potentially any vesicle mitochondria by impairing both kinesin and dynein-­mediated
that relies on ATP generated by glycolysis. movement.181 Fractionation studies in ­Drosophila suggested
Since HTT influences both kinesin-1 and dynein motors a physical association between cytoplasmic dynein and
via a series of different complexes that include Rab proteins164 mitochondria, and mutations in DHC-altered mitochondrial
and BDNF,157 it is not surprising that misregulation of these retrograde transport.89 Furthermore, dynein colocalized with
HTT vesicular complexes could also lead to an impairment mitochondria in both anterograde and retrograde ­directions.184
of axonal transport, which may be an early trigger in disease Although a physical ­association between dynein and Miro
pathology. Expression of mutant HTT also caused neuritic is unknown, together, these studies suggest that dynein is a
aggregates, which blocked protein transport in neurites and key player in the retrograde transport of mitochondria. Fur-
caused neuritic degeneration before nuclear DNA fragmen- thermore, the Drosophila homolog of JIP1, APP-like protein
tation occurred. Simultaneously, expression of cytoplasmic interacting protein 1 (APLIP1), has also been implicated in
polyQ proteins resulted in axonal blockages, retinal degen- mitochondrial transport.185 While a mutation in APLIP1 caused
eration, and larval lethality in a Drosophila model of HD.9 larval paralysis, swelling in axons, and reduced both antero-
Together, these studies suggest that the early neuropathology grade and retrograde vesicle transport,185 only the retrograde
of HD can originate from axonal dysfunction mediated by transport of mitochondria was decreased, suggesting an inhibi-
defects in axonal transport. Indeed, mutant HTT can activate tion of the dynein motor. However, it remains unclear whether
JNK3 (a neuronal specific c-Jun kinase) that phosphorylates APLP1 acts as an adaptor for the dynein-mediated retrograde
the kinesin-1 motor, resulting in the disassociation of kinesin transport of mitochondria. Perhaps several adaptor proteins
from MTs172 (Figure 3C) perturbing transport. may link mitochondria to dynein.186
Several proteins have been implicated in the regulation of
Mitochondria complex mitochondrial movement187–190 (Figure 4B). Mitofusins (Mfn1
Distal compartments, such as synapses, depend on and Mfn2), which are located on the outer ­membrane of
mitochondrial transport to supply ATP for cellular processes ­mitochondria187 and are essential for mitochondria fusion,191,192
like synaptic transmission.173 Mitochondria is known to are thought to be involved in ­mitochondrial transport.187
undergo both anterograde and retrograde transport89,174,175 Biochemical evidence suggested that Mfn1/Mfn2 interacts

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Anderson et al Dovepress

A B C age of motile mitochondria, while overexpression abolished

motility.195 Furthermore, neuronal activity and Ca2+ promoted
the recruitment of SNPH to mitochondria and was neces-

M
Miro

fn
PINK1

2
n

sary to maintain the balance between stationary and mobile

Milto

Parkin

SNPH
mitochondria.196 Together, these observations propose an
engine-switch- and-brake model, in which SNPH may func-
− + tion as an engine-off switch by sensing Miro-Ca2+ and as a
brake by anchoring mitochondria to MTs.196
D
While little is known about the regulatory mechanisms
OR
of mitochondrial motility, work has shown that Ca2+ may be
Miro
Ca2+
important. Miro contains two EF-hand Ca2+ binding domains
n
Milto

and is a Ca2+ sensor that regulates mitochondrial motil-

ity.176,186,197–199 While the assembly of the KHC-Milton-Miro
protein complex increased mitochondrial motility along
− +
axons, elevated cytosolic Ca2+, as a result of neuronal activity
Figure 4 Proposed models of mitochondrial cargo complexes and their regulation inhibited mitochondrial motility. The inhibition of mitochon-
during transport.
Notes: (A) Rho-GTPase Miro and Milton form a complex in which Milton serves drial motility in neurons with Miro mutations in the two EF
as an adaptor to link the Miro/mitochondria complex to KHC. (B) Mfn2 associates hands that cannot bind Ca2+ 197,198 suggests that Miro-mediated
with the Miro/Milton complex. PINK1 phosphorylates Miro at S156 to release
damaged mitochondria from kinesin-1. (C) SNPH acts as an anchor to halt transport Ca2+ levels play a key role in the regulation of mitochondrial
of mitochondria in the presence of Ca2+. (D) Ca2+ binding to the EF-hand helix– motility. Perhaps a Miro-Ca2+ sensing mechanism exists
loop–helix structural domain of Miro induces KHC to bind Miro instead of MT or
Ca2+ binding to Miro detaches the Milton/Miro complex from KHC, resulting in whereby the binding of Ca2+ to Miro releases KHC from
mitochondria to becoming stationary.
mitochondria181,186,197 (Figure 4D).
Abbreviations: GTP, guanosine triphosphate; Mfn, mitofusin; KHC, kinesin heavy
chain; PINK, PTEN induced kinase 1; SNPH, syntaphilin; MT, microtubules. Interestingly, impairment in mitochondrial transport
has been observed in many neurodegenerative diseases,
with the Milton/Miro complex.187 Furthermore, defects in such as AD. 200–202 Impaired mitochondrial motility is
anterograde and retrograde mitochondrial transport were seen observed in Aβ-rich environments, 203–206,208 implicating
in neurons from mice with a knockout of Mfn2 or mice with axonal ­mitochondrial changes in synaptic dysfunction in
a Charcot–Marie–Tooth (CMT2a) disease mutant in Mfn2 AD ­neurons. Interestingly, in vitro studies in hippocampal
(R94Q),187 suggesting that Mfn has a role in mitochondrial neurons indicate a potential role for PKA and GSK-3β on
motility. Another mitochondrial-associated protein, PINK1, Aβ and its action on mitochondrial transport.207 While the
has been proposed to form a multiprotein complex with inhibition of PKA had no effect on Aβ-mediated mitochon-
­Milton/Miro.193 Biochemical and genetic evidence indicated drial transport, activation via forskolin completely eliminated
that Miro/Milton and PINK1 could interact with each other.185 mitochondrial transport defects induced by Aβ. On the other
Furthermore, PINK1 can regulate mitochondrial motility hand, GSK-3β inhibition via lithium also completely abol-
in motor neurons.194 Overexpression of PINK1 decreased ished Aβ-induced mitochondrial defects,208 while excess of
mitochondrial flux and velocities in both directions, while GSK-3β inhibited the bidirectional movement of mitochon-
the loss of PINK1 had the opposite effect. Altering PINK1 dria in vivo.208 Similarly, Aβ oligomers impaired mitochon-
activity with RNA interference affected the distribution of drial motility in hippocampal neurons, which appeared to be
mitochondria in motor neuron axons.194 Interestingly, Wang mediated by N-methyl-D-aspartate receptors.203
et al suggested that PINK1 can phosphorylate Miro on Considering that PKA inhibits GSK-3β via phospho-
Ser156, and this can activate the proteasomal ­degradation of rylation,207 and GSK-3β affects the phosphorylation state
Miro in a parkin-dependent manner.189 Perhaps removal of of KHC,209 a potential mechanism may exist whereby PKA
Miro via proteasomal degradation is a potential mechanism suppresses Aβ-induced mitochondrial transport defects by
for the detachment of kinesin motors from mitochondria, modulating GSK-3β activity.
targeting dysfunctional mitochondria for mitophagy.189 Work has also shown mitochondrial transport defects
­Additionally, syntaphilin (SNPH), an axonally targeted pro- in HD.210–212 Mitochondria were progressively immobilized
tein, was identified as a mitochondria-docking receptor to with frequent stops in neurons from HD transgenic animals,
MTs (Figure 4C). Deletion of SNPH increased the percent- and these defects occurred early during development prior

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Dovepress Axonal transport and diseases

to the onset of measurable neurological or mitochondrial FMRP was found in the same complex as KHC in mouse
abnormalities.210 Further, changes in the levels of electron ­homogenates.224 The Drosophila homolog of FMRP, dFMRP,
transport chain genes and mitochondrial structural genes were was shown to associate with both KHC and DHC and the
thought to be responsible for the abnormal mitochondrial RNAi knockdown of either motor blocked transport of FMRP-
dynamics observed in the cortices of HD patients.211 ­Moreover, containing granules.225 Moreover, while one study found that
mutant HTT associated with the mitochondrial protein Drp1 the FMRP interaction with kinesin-1 was specific to KHC
influenced axonal transport.212 Perhaps mutant HTT may and not KLC,225 another study showed that the C-­terminal
induce aberrant associations that impair mitochondrial dynam- domain of FMRP can directly interact with KLC.226 Together,
ics, decreasing mitochondrial function in HD. these studies indicate that both motors are required for the
transport of FMRP within axons. ­Furthermore, FMRP is
RNA cargo complex thought to negatively regulate the number of mitochondria
Several lines of evidence suggest that molecular motors in axons and in neuromuscular junction synapses, affecting
are responsible for the spatial localization of RNA, which mitochondrial flux and processivity.227
regulates protein production at specific sites within a cell.213 Work on the La RNA chaperone protein exposed an
In Drosophila oocytes, kinesin-1 is responsible for the interesting mechanism for RNA transport.228 In dorsal root
transport of Oskar messenger RNA (mRNA) to the pos- ganglion neurons, sumoylation of La at lysine 41 was essential
terior pole,214,215 while dynein mediates the anterior-dorsal for its interaction with dynein but not kinesin.228 Furthermore,
­localization of gurken mRNA and anterior localization of sumoylated La moved retrogradely in ligated sciatic nerves
bicoid mRNA.216,217 Similarly, intracellular mRNA localiza- from adult rats causing distal accumulations of sumoylated
tion is also a conserved mechanism for spatially regulating La.228 This study suggests that modifying protein–protein
protein production in polarized neurons since local transla- interactions may control the directionality of RNA transport
tion of mRNAs is thought to be essential for many neuronal via sumoylation and may constitute an important regulatory
functions, such as the regulation of axon growth, axon main- mechanism. However, whether this is the central mechanism
tenance, and regeneration after axonal injury. that governs all RNA transport is unclear, given that only a few
Recent imaging studies have shown that distinct mRNA- RNA-binding proteins have been shown to undergo sumoyla-
containing complexes, including granules and mitochondrial tion.229 Thus, it is becoming evident that long-distance mRNA
mRNA, are transported long distances within neuronal transport requires microtubule-dependent motors, but the
­projections.218 Neuronal RNA granules are essentially ribonu- molecular mechanisms underlying the sorting and trafficking
cleoprotein particles whose roles involve transporting mRNA of mRNAs into axons or dendrites remains elusive. While the
along MTs and modulating local protein synthesis in response roles of RNPs are still unclear, their sequestration into trans-
to synaptic activity.219–221 Further, the mRNA encoding the ported RNP particles and their specific localization is likely
translational repressor Nanos (nos) forms ribonucleoprotein the result of specific targeting rather than passive diffusion.
(RNP) particles that are dendritically localized in dendritic Therefore, local translation of RNA must be a rapid response
arborization neurons in Drosophila.222 mechanism to signals at the synapses to mediate synaptic
Interestingly, the RNA-binding protein Rumpelstiltskin plasticity230–232 during development and regeneration.
and the germ plasm protein Oskar, also functions in dopamin-
ergic neurons to assemble and to transport nosRNP particles Other cargo complexes
mediated by dynein.222 Although the exact mechanisms Many more potential disease protein complexes are emerging
of how these RNP complexes associate with kinesin-1 or that may rely on axonal transport to maintain their normal
dynein for localization is still unclear, these studies show functions in neurons. Two of these are briefly discussed.
that localization factors are adaptable and can regulate and
target transcripts in different cellular contexts. Potential spinal muscular atrophy
Biochemical, imaging, and immunofluorescence studies (SMA)-cargo complex
on the Fragile X mental retardation (FMR) mRNA com- The survival motor neuron (SMN) protein is vital for the mat-
plex have provided evidence for its involvement in axonal uration of small nuclear ribonucleoproteins233 and, ­possibly,
­transport. FMR mRNA, which encodes the Fragile X mental the functional localization of messenger RNPs.234 Lack of
retardation protein (FMRP), forms granules containing SMN due to SMN deletion is one cause of SMA. Although it
its own RNA and moves along neurites.223 ­Interestingly, is unclear what complexes SMN is a part of, SMN has been

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Anderson et al Dovepress

found in axonal termini and growth cones.235 Furthermore, shown that TDP-43 is localized and actively transported
SMN granules were observed to be transported in cultured in motor neuron axons and colocalizes with well-studied
primary neurons with speeds that were consistent with fast axonal mRNA-binding proteins, such as FMRP, HuD, and
axonal transport (1.8 µms–1).236 Since associations between SMN.250
SMN and mRNA binding proteins HuD240 and FMRP241 Perhaps similar to SMA, a TDP-43-RNA complex also
have been shown, perhaps SMN functions in RNA motility. exists. These observations suggest that TDP-43 has an
Interestingly, several mutations in the tail domain of DHC important role in the regulation of axonal growth, and that
(DYNC1H1) that disrupt dynein function have been found in impairment in the posttranscriptional regulation of mRNAs
patients with SMA.237 More recently, two other mutations in in the cytoplasm of motor neurons may be a major factor in
the neck and motor domain of dynein were associated with the development of ALS.
SMA.238 Interestingly, pharmacological compounds known
to rescue kinesin-mediated larval locomotion in Drosophila Summary
stimulated neurite growth in rat spinal neurons and rescued It is intriguing that a vast majority of disease-related proteins
motor neuron development in a Zebra fish model of SMA.239 have been shown to interact with molecular motors or to
Taken together, these observations suggest that SMN has be present on transported cargo complexes. Many of these
a role in axonal transport and may form the unique cargo disease-related proteins also have roles – either during axonal
complex that interacts with MT motors. transport or they are dependent on axonal transport for their
proper localization and function. Further, the motility of these
Potential ALS-cargo complex cargo complexes appears to be highly regulated at many ­levels;
ALS is a motor neuron disease caused by mutations in sev- regulation of the motors themselves and the regulation of
eral genes, including SOD1 and TDP-43. Recent work has the association of these complexes with motors by a myriad
shown that mutant superoxide dismutase (SOD1) can induce of adaptor proteins and/or post translational modifications.­
defects in axonal transport.249 KAP3 (kinesin-associated Moreover, in some diseases where more than one gene or pro-
protein 3), a subunit of the kinesin 2 family, was shown to tein is involved in causing the disease, all of the disease proteins
bind misfolded-mutant SOD1.244 KAP3 is known to bind to appear to converge in the axonal transport pathway. Either they
choline acetyltransferase (ChAT), which requires kinesin-2 for are contained in the same vesicle or they are in different types
transport in axons.242,243 Tateno et al suggested that misfolded of vesicle or RNA granules. Thus highlighting the importance
SOD1 was able to sequester kinesin-2 motors and impair ChAT of the axonal transport pathway and implicating perturbations
transport.244 Indeed, a similar mechanism, the impairment of in axonal transport in the initiation and progression of many
axonal transport via sequestration of motors, was previously neurodegenerative diseases. Therefore, it is not surprising that
proposed in a Drosophila model of HD9 and was recently mutations in motor proteins cause neurodegeneration defects
theorized to occur in ALS through computational analysis.245 in transport have been shown to precede behavioral defects and
Computational analysis indicated that defects in axonal trans- neuropathology in many human neurodegenerative diseases.
port in SOD1 models of ALS result in protein aggregation and Thus, unraveling the identity of these motor-cargo complexes,
motor depletion. Furthermore, it was also shown that misfolded the mechanisms of transport and how normal disease protein
SOD1 impaired acetylcholine release, which was rescued via complexes function are all critical in understanding how prob-
overexpression of KAP3.244 Together, these results suggest that lems in transport contribute to disease states. Such analysis has
disrupting the transport of acetylcholine- and ChAT-containing important implications for potential early diagnosis of neuronal
vesicles may lead to aberrant protein accumulations, leading disease and for the development of therapeutic interventions
to the progression of ALS, postulating a ChAT/acetylcholine before the onset of neuronal death.
cargo complex in the context of ALS.
Alternatively, similar to SMA, disruption in RNA trans- Acknowledgments
port could also lead to the progression of ALS. A pathologi- The authors regret that space limitations restricted some
cal hallmark of ALS is the cytoplasmic inclusions containing work from being cited. The authors thank members of the
hyperphosphorylated and ubiquitinated TDP-43.251 TDP-43 Gunawardena Laboratory at the State University of New
is a ubiquitous DNA/RNA-binding protein with a nuclear York at Buffalo, NY, USA for helpful discussions. SG
role in pre-mRNA splicing, and mutations have recently thanks Priyantha Karunaratne for constant support. SG is
been linked to the development of ALS.250 Recent work has funded by the John R Oishei Foundation, Buffalo, NY, USA,

40 submit your manuscript | www.dovepress.com Degenerative Neurological and Neuromuscular Disease 2014:4
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Dovepress Axonal transport and diseases

and the National Institutes of Health/National Institute of 20. Xia CH, Rahman A, Yang Z, Goldstein LS. Chromosomal localiza-
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