. "Kinesin molecular motors: Transport pathways, receptors, and human disease." (NAS Colloquium) Molecular Kinesis in Cellular Function and Plasticity. Washington, DC: The National Academies Press, 2002.
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Colloquium on Molecular Kinesis in Cellular Function and Plasticity
axonal, dendritic, synaptic, or cell body compartment, and why Aß is neurotoxic.
Several groups have suggested that axonal transport defects may occur later in the pathogenesis of the disease (e.g., ref. 53), but have left unanswered the question of whether it might be an initiating event as well. Could the transport function of APP be related to the initiation or progression of Alzheimer’s disease? Several observations suggest that the answer to this question could be yes. First, as just discussed, normal transport of the APP protein in mammalian axons appears to depend on a direct interaction with the KLC subunit of the kinesin-I molecular motor protein (37). Thus, the disease causing protein may have a kinesin-I receptor function and thus be in close apposition to the transport machinery. Second, overexpression of the Drosophila homologue of APP called APPL in Drosophila (54) causes axonal clogs analogous to those found in syd and many other mutants with defective axonal transport. Perhaps overexpression of a protein such as APP with a motor receptor function either titrates out needed kinesin motor function in the axon or unbalances traffic in these narrow caliber axons leading to transport dysfunction, clogging, and other abnormalities. Third, humans bearing trisomy 21 suffer from premature onset of the symptoms characteristic of Alzheimer’s disease, perhaps because of overproduction of Aß (55). Although other genes are clearly present in excess in trisomy 21, it is striking that the gene encoding APP is located on chromosome 21 and thus is certainly one of the genes overexpressed in these people. Experiments in mouse models that overexpress APP have given equivocal results, but in some cases similar phenotypes have been reported (reviewed in ref. 56). Fourth, one of the early phenotypes of mouse models of Alzheimer’s disease, and perhaps human Alzheimer’s disease, is “dystrophic neurites,” whose morphology includes organelle and vesicle accumulations in axons (e.g., ref. 57). This phenotype is strikingly reminiscent of the axonal clogging observed after disturbance of axonal transport in Drosophila. Fifth, while it is unclear where in neurons Aß production is prominent, it is striking that even though APP is widely expressed, Alzheimer’s disease is primarily a neuronal disease. One feature that sets neurons apart from other cells is long axonal and dendritic processes. That a critical function of these processes is movement and transport of vesicular cargoes may be important to the development of disease.
How could alterations in axonal transport of APP lead to the generation of excess Aß and Alzheimer’s disease? Perhaps enhanced proteolysis of APP caused by axonal damage, presenilin or APP mutations, or elevated APP levels, cause impairments of APP transport efficiency in axons and increase the time spent by APP and proteases in a common axonal vesicular transport compartment. Time-dependent or damage-induced generation and accumulation of Aß by proteolysis of APP in this compartment might lead to aggregates of Aß that impair or block axonal transport and further stimulate Aß production in an autocatalytic spiral. Such a process could lead to neuronal dysfunction and progressive, age-related neurodegeneration and disease. In fact, although not measured directly by any researcher, it is possible that the populations of neurons affected first in Alzheimer’s disease could be those that combine the narrowest caliber with a higher than usual transport burden. Such features might predispose these axons to aggregation, or reduction in velocity, of their axonal transport cargoes, analogous to what has been observed in genetic models of axonal transport disturbance in Drosophila. Ultimately, neurotrophic signaling in neurons could be blocked by formation of axonal clogs, leading to apoptotic neuronal cell death. This proposal also may explain why some people appear to be more susceptible to Alzheimer’s disease than others. Perhaps the degree of axonal branching and caliber and perhaps allelic state at crucial molecular motor subunit genes will be found to be important once explored. If correct, this view also can account for the observation that it generally takes decades for Alzheimer’s disease to develop. Slight decrements in transport rate or efficiency could lead to slightly enhanced proteolysis rates that will in turn eventually lead to Alzheimer’s disease. Clearly, further work to test these ideas is needed.
We may be at the beginning of an era in which neuronal transport is recognized as a major cellular target for the development of neurodegenerative disease. Although ciliary dyskinesias, retinitis pigmentosa, and Alzheimer’s disease are the major examples discussed above, there are also suggestions that amyotrophic lateral sclerosis may be caused or complicated by transport defects in motor neurons (58, 59). Similarly, it may be more than a coincidence that huntingtin, tau, and ApoE4, all of which are implicated in causation or susceptibility to neurodegenerative disease, all have been suggested to modulate transport when experimentally manipulated or to interact directly with the transport machinery (60–65). Finally, it is possible that for those neurodegenerative diseases in which formation of aggregates is an important feature, inhibition of axonal transport by the aggregates may be an important element in disease progression. In this regard, a recent report that axonal blockages and possible impairment of axonal transport may be present in CreutzfeldtJacob disease is intriguing (66).
I am an Investigator of the Howard Hughes Medical Institute. Some of the work discussed in this article was supported by National Institutes of Health Grant GM35252.
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