Long-projecting neurons are particularly dependent on efficient intracellular transport because their distal axonal regions are far from the cell body. Proteins, RNAs, vesicles, mitochondria and other organelles need to move toward these regions, while damaged organelles and signaling molecules must also return toward the soma. Much of this bidirectional transport depends on the microtubule cytoskeleton and the motor proteins that move along it. What matters is not simply how fast a cargo moves, but whether it reaches the right place at the right time [1].

Defects in axonal transport have been reported in several neurological disorders, including hereditary spastic paraplegia, amyotrophic lateral sclerosis, Huntington’s disease, Alzheimer’s disease and inherited peripheral neuropathies [2]. These diseases have different genetic and molecular causes; transport dysfunction is not necessarily the same process in each. Here, SPG4, FUS-associated ALS and Huntington’s disease are selected examples, not an exhaustive account of these disorders.

What they may share instead is a dependence on the same cellular system. Once intracellular transport is disturbed, maintaining a long axon becomes increasingly difficult.

Why are long axons particularly vulnerable?

Microtubules provide the main tracks for long-distance transport within axons. Kinesin motors predominantly carry cargo toward distal axonal regions, whereas dynein transports cargo back toward the cell body. Different cargoes have different requirements, and movement can also include pausing or local retention [1].

Efficient transport depends on more than functional motor proteins. The organization of the microtubule network, interactions between motors and their cargoes, organelle positioning and local energy supply all contribute to the process. A disturbance at any of these levels can affect cargo distribution within the axon.

This becomes especially important over long distances. Mitochondria, for example, need to reach regions with high energy demand. They do not necessarily have to be intrinsically dysfunctional to create a local problem; failure to reach the appropriate part of the axon may already compromise local function. Transport in the opposite direction is equally important because damaged organelles and signaling cargoes must return toward the cell body.

Transport defects may not cause immediate degeneration. Neurons can compensate for moderate disturbances for considerable periods, particularly in slowly progressive diseases. However, this capacity may eventually become insufficient to maintain distal axonal regions.

This dependence on continuous transport is one reason why long-projecting neurons may be particularly vulnerable in neurodegenerative disease [2].

SPG4 provides a useful example

Hereditary spastic paraplegias illustrate how different cellular defects can converge on long-axon maintenance. Although HSP is genetically heterogeneous, many HSP-associated proteins participate in processes such as intracellular trafficking, organelle organization, cytoskeletal regulation, mitochondrial function and protein degradation [3].

SPG4 is caused by mutations in SPAST, which encodes the microtubule-severing protein spastin. The disease predominantly affects long corticospinal axons and leads to progressive lower-limb spasticity and gait impairment [4].

Spastin does not simply dismantle microtubules. Controlled severing helps remodel the network, so changes in spastin activity can also affect the tracks used for cargo movement [4].

In a spastin-mutant mouse model, anterograde movement of mitochondria and APP-containing organelles was impaired. In neurons with axonal swellings, mitochondrial movement in both directions was strongly reduced distal to the swellings [5].

There is also another route to transport dysfunction in SPG4. Mutant M1-Spastin can inhibit fast axonal transport through casein kinase 2 (CK2) activation, independently of its microtubule-binding or severing activity [6]. These findings show how altered microtubule regulation and mutant-protein toxicity can affect transport through distinct mechanisms within the same disease.

When does a transport defect become part of the disease?

One difficulty is determining whether impaired transport is a cause or a consequence of neurodegeneration.

The answer is unlikely to be the same in every disease. In some experimental models, transport abnormalities appear relatively early and may contribute directly to pathology. In others, they arise after other cellular changes have already begun [2].

However, a secondary transport defect can still become relevant to disease progression. Reduced mitochondrial delivery can increase local energy stress, while reduced energy availability can further limit active transport. Failure to remove damaged organelles or proteins can increase cellular stress. Changes in cytoskeletal organization may then further compromise cargo movement.

These processes can therefore reinforce one another.

For this reason, whether transport dysfunction is the first pathological event may be less important therapeutically than whether it becomes a reversible contributor to subsequent axonal dysfunction.

Can axonal transport be targeted?

The possibility of targeting axonal transport is attractive, but transport cannot simply be increased globally. Different cargoes need to move in different directions, stop at specific locations and sometimes remain anchored. Restoring transport therefore means restoring the appropriate movement of the relevant cargo rather than simply making transport faster.

Changes in microtubule acetylation provide one example. HDAC6 regulates α-tubulin deacetylation and has been investigated as a way to modify the microtubule environment in neurological disease.

In motor neurons derived from patients with FUS-associated ALS, axonal transport defects developed progressively. Pharmacological inhibition or genetic silencing of HDAC6 increased α-tubulin acetylation and reversed the transport defects [7]. This shows that a transport phenotype can be reversible in cultured neurons, but it does not establish that the same intervention would slow disease progression in patients.

But increasing tubulin acetylation does not always produce the same outcome. In the R6/2 mouse model of Huntington’s disease, deletion of HDAC6 substantially increased tubulin acetylation but did not improve disease progression or restore BDNF transport [8]. More recent work with the selective inhibitor CKD-504, however, reported improved mitochondrial transport in neural stem cells derived from YAC128 mice and improved behavioral outcomes in the mice themselves. [9] These findings come from different models and interventions, so neither should be treated as a general verdict on HDAC6 as a target.

More recently, the HDAC6 inhibitor EKZ-438 improved axonal transport and motor performance in SOD1 mutant mice, as well as intracellular transport in human TARDBP-mutant neurons [10]. These results are encouraging, but whether the intervention can slow disease progression in patients remains unknown. Together, the studies suggest that axonal transport cannot be treated as one uniform therapeutic target.

The relevant questions are more specific: Which cargo is affected? Is movement toward or away from the cell body altered? Where in the axon does the defect occur? At what stage of disease does it appear? And is it still reversible at that point?

Mitochondria, lysosomes, signaling endosomes and synaptic components have different transport requirements. Recent work in stem-cell-derived Huntington’s disease neurons found that expanded huntingtin could misdirect BDNF endosomes and alter the recruitment of their motor proteins [11]. Greater cargo movement is therefore not always more useful movement. A treatment that improves the movement of one cargo may have little effect on another.

A shared vulnerability rather than a shared cause

Axonal transport is unlikely to be a single disease mechanism shared by SPG4, ALS, Huntington’s disease or other neurological disorders. Their initiating molecular defects remain distinct.

A more useful interpretation may be that long axons share a strong dependence on efficient intracellular transport, and different diseases can expose this same vulnerability.

This distinction changes how axonal transport might be considered therapeutically. A transport-directed intervention would not necessarily correct the primary mutation or remove the initiating pathology. Its role may instead be to preserve distal axonal function and delay the stage at which compensatory mechanisms become insufficient.

For slowly progressive disorders, this could still be meaningful. Disease-specific treatments might eventually be combined with approaches that support the cellular processes required for long-term axonal maintenance.

The next challenge is therefore not simply to identify more diseases with transport abnormalities. It is to determine which cargo-specific defects actively contribute to degeneration, appear early enough to target and remain reversible. Longitudinal measurements that distinguish cargo identity, direction, pausing and location along the axon, together with measures of neuronal function, will be important for answering these questions.

Different neurological diseases may begin with different molecular defects, but long axons may still become vulnerable through some of the same downstream processes.

References

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