Where does slow axonal transport go?

doi:10.1016/j.neures.2003.08.005

Neuroscience Research

Volume 47, Issue 4, December 2003, Pages 367-372

https://doi.org/10.1016/j.neures.2003.08.005 Get rights and content

Abstract

Axonal transport is the specialized and well-developed intracellular transport system for regulated and/or long-distance transport based on generalized cellular machineries. Among them, slow axonal transport conveys cytoplasmic proteins. The motor molecule, the nature of transporting complex and the transport regulation mechanism for slow transport are still unclarified. There has been a dispute regarding the nature of transporting complex of cytoskeletal proteins, polymer-sliding hypothesis versus subunit-transport theory. Recent data supporting the hypothesis of polymer sliding in cultured neurons only reconfirm the previously reported structure and this inference suffers from the lack of ultrastructural evidence and the direct relevance to the physiological slow transport phenomenon in vivo. Observation of the moving cytoskeletal proteins in vivo using transgenic mice or squid giant axons revealed that subunits do move in a microtubule-dependent manner, strongly indicating the involvement of microtubule-based motor kinesin. If the slow transport rate reflects the intermittent fast transport dependent on kinesin motor, we have to investigate the molecular constituents of the transporting complex in more detail and evaluate why the motor and cargo interaction is so unstable. This kind of weak and fluctuating interaction between various molecular pairs could not be detected by conventional techniques, thus necessitating the establishment of a new experimental system before approaching the molecular regulation problem.

Section snippets

Physiological significance of the slow axonal transport: a brief overview

Cells are not merely composed of homogenous viscous substances covered with lipid membranes. Thousands of molecules are interacting with each other incessantly, and some kinds of direct interaction of the molecules always precede specific biological actions. To interact with each other, biological molecules have to gather together in a highly orchestrated manner. Each player has to be transported to the right place at the right time, and the essence of life resides in dynamic system. In the

Disputes regarding the molecular mechanism of slow axonal transport: nature of transporting complex

The enigmas of slow axonal transport could be summed up in the following three points: motor molecule, nature of transporting complex (cargo molecules) and the regulation mechanism of the transport (Terada and Hirokawa, 2000).

Regarding the nature of transporting complex, the precise composition and relationship between quality control of transporting proteins and transport mechanism has been the subject of intense scrutiny. Lasek’s group insisted that the main slow transport contents,

The enigma with partial solution: motor molecule for slow axonal transport

In contrast to the discovery of kinesin as a fast axonal transport of membranous organelles, the motor enzyme for slow axonal transport has been enigmatic. Cytoplasmic proteins are conveyed at the speed of less than 8 mm a day, more than one order slower speed than that of simple diffusion. This slowness precludes usual cell biological and microscopic observation like video-enhanced microscopy or in vitro reconstitution experiment; we could not discriminate active and directed but slow transport

The enigma remaining and the future direction

Compared with the conundrum of the motor molecule and the nature of transporting complex, the molecular mechanism for the regulation of slow axonal transport still remains unclarified. Before we approach the molecular regulation problem, we have to investigate the molecular constituents of the transporting complex in more detail. To solve the mystery, we need some innovative experimental system to detect the weak interaction among biological molecules in a wholistic manner, because

Acknowledgements

The author would like to thank Drs. S. Takeda and N. Hirokawa (Tokyo University) for critical reading of the manuscript, helpful discussion and proper guidance throughout the project. The author would also like to thank collaborators and many members of Hirokawa’s laboratory for help and discussions. Part of the work presented here is supported by a Special Grant-in-Aid for Center of Excellence from the Japan Ministry of Education, Culture, Sports, Science and Technology to N. Hirokawa. Due to

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Citation Excerpt :
Although the mechanism underlying axonal TH transport is not fully understood, the projection from SNc to the striatum in mice is about 2–10 mm, depending on axonal branching (22, 23). The axonal transport of TH was reported to be about 2 mm/h in chicken sciatic nerves (32), but it could be different in the brain because the cytosolic proteins are delivered by the slow axonal transport system at 0.1–8 mm/day (33, 34). These reports raise a possibility that it takes a week or more to transport TH proteins from a soma to axon terminals in the mouse nigrostriatal projection.
The tyrosine hydroxylase (TH; EC 1.14.16.2) is a rate-limiting enzyme in the dopamine synthesis and important for the central dopaminergic system, which controls voluntary movements and reward-dependent behaviors. Here, to further explore the regulatory mechanism of dopamine levels by TH in adult mouse brains, we employed a genetic method to inactivate the Th gene in the nigrostriatal projection using the Cre-loxP system. Stereotaxic injection of adeno-associated virus expressing Cre recombinase (AAV-Cre) into the substantia nigra pars compacta (SNc), where dopaminergic cell bodies locate, specifically inactivated the Th gene. Whereas the number of TH-expressing cells decreased to less than 40% in the SNc 2 weeks after the AAV-Cre injection, the striatal TH protein level decreased to 75%, 50%, and 39% at 2, 4, and 8 weeks, respectively, after the injection. Thus, unexpectedly, the reduction of TH protein in the striatum, where SNc dopaminergic axons innervate densely, was slower than in the SNc. Moreover, despite the essential requirement of TH for dopamine synthesis, the striatal dopamine contents were only moderately decreased, to 70% even 8 weeks after AAV-Cre injection. Concurrently, in vivo synthesis activity of l-dihydroxyphenylalanine, the dopamine precursor, per TH protein level was augmented, suggesting up-regulation of dopamine synthesis activity in the intact nigrostriatal axons. Collectively, our conditional Th gene targeting method demonstrates two regulatory mechanisms of TH in axon terminals for dopamine homeostasis in vivo: local regulation of TH protein amount independent of soma and trans-axonal regulation of apparent l-dihydroxyphenylalanine synthesis activity per TH protein.
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While the phenomenon of slow axonal transport is widely agreed upon, its underlying mechanism has been controversial for decades. There is now persuasive evidence that several different mechanisms could contribute to slow axonal transport. Yet proponents of different theories have been hesitant to explicitly integrate what were, at least initially, opposing models. We suggest that slow transport is a multivariate phenomenon that arises through mechanisms that minimally include: molecular motor-based transport of polymers and soluble proteins as multi-protein complexes; diffusion; and en bloc transport of the axonal framework by low velocity transport and towed growth (due to increases in body size). In addition to integrating previously described mechanisms of transport, we further suggest that only a subset of transport modes operate in a given neuron depending on the region, length, species, cell type, and developmental stage. We believe that this multivariate approach to slow axonal transport better explains its complex phenomenology: including its bi-directionality; the differing velocities of transport depending on cargo, as well differing velocities due to anatomy, cell type and developmental stage.
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Abstract

Section snippets

Physiological significance of the slow axonal transport: a brief overview

Disputes regarding the molecular mechanism of slow axonal transport: nature of transporting complex

The enigma with partial solution: motor molecule for slow axonal transport

The enigma remaining and the future direction

Acknowledgements

Trends Cell Biol.

Trend Cell Biol.

Curr. Opin. Neurobiol.

Cell

Curr. Biol.

Transport and turnover of microtubules in frog neurons depend on the pattern of axonal growth

J. Neurosci.

Speckle microscopic evaluation of microtubule transport in growing nerve processes

Nat. Cell Biol.

Active transport of photoactivated tubulin molecules in growing axons revealed by a new electron microscopic analysis

J. Cell Biol.

Intracellular-transport in neurons

Physiol. Rev.

Rapidly transported organelles containing membrane and cytoskeletal components: their relation to axonal growth

J. Cell Biol.

Rapid mobility of motile varicosities and inclusions containing alpha-spectrin, actin, and calmodulin in regenerating axons in vitro

J. Neurosci.

Axonal-transport of the cytoplasmic matrix

J. Cell Biol.

Update article
Where does slow axonal transport go?