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Impaired axonial transport leads to Sensory axonal peripheral neuropathy
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Microtubule interacting drugs lead to peripheral neuropathy||adjacent||Not Specified||Not Specified||Arthur Author (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Evidence Supporting this KER
Defects in axonal transport are often suggested as a cause for peripheral neuropathies as the length-dependent, distal neurologic deficits observed in patients treated with taxol or other MSAs indicate an axonal loss comparable to dying-back neuropathies which are often linked to axonal transport defects. 
Mutations linked to axonal transport are known to cause Charcot-Marie-Tooth disease (peripheral neuropathy). A mutation in the gene coding for the motor protein kinesin 1B (KIF1B) was found in a CMT2A family. The transport of synaptic vesicles is mediated by KIF1B. 
Generated KIF1A mutant mice exhibited motor and sensory disturbances and transport of synaptic vesicle precursors was shown to be decreased in axons. 
Uncertainties and Inconsistencies
The KIF1B mutation, which was identified in a CMT2A family and proven to disturb axonal transport, was only found in this family and has never been confirmed. [2, 6]
KIF1A knockout mice were born alive but died within 24h after birth. All measurements of sensory and motor function, axonal degeneration and axonal transport were performed within these 24h. 
Neuropathy was induced in cats by administration of either acrylamide or triorthocresyl phosphate (TOCP). Neuropathic symptoms like axonal degeneration were detected in both acrylamide- as well as TOCP-induced neuropathic cats but axonal transport of proteins was shown to be disturbed only in acrylamide-induced neuropathic cats. 
Furthermore, only limited human in vivo evidence is available for KE1 and its relationship to the AO.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
1. Rowinsky , E.K. and R.C. Donehower Paclitaxel (Taxol). New England Journal of Medicine, 1995. 332(15): p. 1004-1014.
2. Zhao, C., et al., Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell, 2001. 105(5): p. 587-97.
3. Yonekawa, Y., et al., Defect in Synaptic Vesicle Precursor Transport and Neuronal Cell Death in KIF1A Motor Protein–deficient Mice. The Journal of Cell Biology, 1998. 141(2): p. 431-441.
4. Pleasure, D.E., K.C. Mishler, and W.K. Engel, Axonal Transport of Proteins in Experimental Neuropathies. Science, 1969. 166(3904): p. 524-525.
5. Pérez-Ollé, R., et al., Mutations in the neurofilament light gene linked to Charcot-Marie-Tooth disease cause defects in transport. Journal of Neurochemistry, 2005. 93(4): p. 861-874.
6. Pareyson, D., et al., Mitochondrial dynamics and inherited peripheral nerve diseases. Neuroscience Letters, 2015. 596(Supplement C): p. 66-77.