Molecular landmarks along the axonal route: axonal transport in health and disease

doi:10.1016/j.ceb.2008.04.002

Current Opinion in Cell Biology

Volume 20, Issue 4, August 2008, Pages 445-453

https://doi.org/10.1016/j.ceb.2008.04.002 Get rights and content

Axonal transport of organelles has emerged as a key process in the regulation of neuronal differentiation and survival. Several components of this specialised transport machinery, their regulators and vesicular cargoes are mutated or altered in many neurodegenerative conditions. The molecular characterisation of these mechanisms has furthered our understanding of neuronal homeostasis, providing insights into the spatio-temporal control of membrane traffic and signalling in neurons with a precision not achievable in other cellular systems. Here, we summarise the recent advances in the field of axonal trafficking of different organelles, and the essential role of motor and adaptor proteins in this process.

Section snippets

Molecular motors and neurodegeneration

Molecular motors play a major role in axonal transport by moving cargoes along cytoskeletal tracks in an ATP-dependent manner. Three different classes of cellular motors are known: cytoplasmic dynein and kinesins move on microtubules (MT), whereas myosins progress along actin filaments [1, 2]. Crucially, mutations in motor complexes and associated proteins have been found to be linked to neurological disorders (Table 1). Components of the dynein/dynactin complex, a MT minus-end directed motor [1

Endosomal trafficking and signalling in neurons

The transport of endocytic and exocytic compartments along the axon represents one of the main types of organelle trafficking in neurons. Endosomes containing neurotrophins, their receptors, Trks and p75^NTR, and their activated downstream effectors are thought to be responsible for neurotrophin signalling from nerve terminals to the cell body [7]. Several studies have characterised the endosomal trafficking and signalling of neurotrophins. Indeed, it is now believed that specialised endosomes

The role of motor adaptors and anchor proteins in vesicular trafficking in health and disease

The characterisation of novel adaptors involved in vesicular trafficking in neurons has been an area of intense research in the last decade. One of the most studied adaptors is APP, a type I integral membrane protein linked to the pathogenesis of AD [29] and DS [28^••]. AD is characterised by the presence of neurofibrillary tangles of hyperphosphorylated tau and plaques of aggregated β-amyloid (Aβ) peptides in patient brains, which are generated by APP proteolysis.

Several studies have linked AD

The regulation of mitochondrial transport

Consistent with the unique cellular role of mitochondria, their transport is distinct from that of most other organelles [41]. Both their long-distance translocation along MT and their short-range transport along actin filaments (Figure 2) are saltatory and bidirectional [41]. Although at any given time approximately only a third of mitochondria are motile in primary neurons [42], it is well documented that these organelles undergo redistribution in response to intracellular signals and changes

Mitochondrial transport and neuronal homeostasis

Mitochondria occupy a central functional position within neurons, controlling ATP production, cytosolic calcium buffering and apoptosis. The temporal and spatial regulation of mitochondrial transport is therefore essential. Substantial evidence now exists to implicate alterations in mitochondrial transport, in addition to function, in neurodegenerative conditions. Indeed, the anterograde transport of mitochondria is significantly reduced in motor neurons derived from mutant SOD1 mice [42]. The

Additional mechanisms in axonal trafficking

In addition to those described above, mutations of motor and adaptor proteins have been shown to affect other neuronal transport processes, such as RNA trafficking or synaptic dynamics, although an overt link to disease has yet to be established. Recent reports on the axonal transport of specific mRNAs and RNA-binding proteins suggest a fundamental role for local protein synthesis in axonal maintenance and regeneration [59]. This may also be relevant in neurotrophin signalling since NGF

Conclusions

Detailed investigation of the axonal transport of endocytic organelles and mitochondria has enabled a greater understanding of the link between alterations in cellular trafficking and neurological disorders. However, many open questions need to be answered to complete our fragmentary view on the mechanisms controlling axonal transport. The most important is possibly inspired by a quotation from Heraclitus: ‘Are the road up and the road down (the axon) one and the same?’ Indeed, we know very

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We apologise to those authors whose work could not be included in this discussion because of length restrictions. We thank Linda Greensmith for critical reading of the manuscript and Cancer Research UK, Motor Neurone Disease Association and the Jean Coubrough Charitable Trust for funding.

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Axonal transport system is a fundamental platform, necessary for viability of neurons, because of their long extended branches. Disturbed axonal transport will shut down the transport system and neural tissue will collapse rapidly, exactly the same as a town with lack of any transport system in its roads. The most important axonal transport proteins are: kinesin, dynein, and myosin with different types of family member.
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Nervous system function relies on the polarized architecture of neurons, established by directional transport of pre- and postsynaptic cargoes. While delivery of postsynaptic components depends on the secretory pathway, the identity of the membrane compartment(s) supplying presynaptic active zone (AZ) and synaptic vesicle (SV) proteins is unclear. Live imaging in Drosophila larvae and mouse hippocampal neurons provides evidence that presynaptic biogenesis depends on axonal co-transport of SV and AZ proteins in presynaptic lysosome-related vesicles (PLVs). Loss of the lysosomal kinesin adaptor Arl8 results in the accumulation of SV- and AZ-protein-containing vesicles in neuronal cell bodies and a corresponding depletion of SV and AZ components from presynaptic sites, leading to impaired neurotransmission. Conversely, presynaptic function is facilitated upon overexpression of Arl8. Our data reveal an unexpected function for a lysosome-related organelle as an important building block for presynaptic biogenesis.
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Molecular landmarks along the axonal route: axonal transport in health and disease

Section snippets

Molecular motors and neurodegeneration

Endosomal trafficking and signalling in neurons

The role of motor adaptors and anchor proteins in vesicular trafficking in health and disease

The regulation of mitochondrial transport

Mitochondrial transport and neuronal homeostasis

Additional mechanisms in axonal trafficking

Conclusions

References and recommended reading

Acknowledgements

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