API

Relationship: 1835

Title

?

Impaired axonial transport leads to Sensory axonal peripheral neuropathy

Upstream event

?

Impaired axonial transport

Downstream event

?


Sensory axonal peripheral neuropathy

Key Event Relationship Overview

?


AOPs Referencing Relationship

?

AOP Name Adjacency Weight of Evidence Quantitative Understanding
Microtubule interacting drugs lead to peripheral neuropathy adjacent Not Specified Not Specified

Taxonomic Applicability

?

Sex Applicability

?

Life Stage Applicability

?

Key Event Relationship Description

?


Evidence Supporting this KER

?


Biological Plausibility

?

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. [1]

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. [2]

Generated KIF1A mutant mice exhibited motor and sensory disturbances and transport of synaptic vesicle precursors was shown to be decreased in axons. [3]

Empirical Evidence

?

- Mutated KIF1B was shown to lose motor activity and did not move towards the plus end of microtubules. [2] A loss of function in motor proteins leads to disruption of transport along microtubules and therefore also of axonal transport. As this mutation of KIF1B was shown to be linked to CMT2A [2], a peripheral neuropathy, a direct link between axonal transport defects and peripheral neuropathy can be created.

- Transport of the synaptic vesicle precursor synaptotagmin was shown to be decreased in mice with a knockout of the KIF1A motor protein. These mice also exhibited axonal degeneration and showed motor and sensory disturbances. [3]

- Neuropathy was induced in cats by administration of acrylamide. Cats exhibited neuropathic symptoms like foot drop and also axonal degeneration was documented. Axonal transport was proven to be disturbed in acrylamide-neuropathic cats. [4]

- Several mutations in the neurofilament light (NFL) gene have been shown to cause Charcot-Marie-Tooth disease, a peripheral neuropathy. Neuronal cultures of NFL mutants exhibited reduced axonal transport. Furthermore, mutant NFL protein overexpression lead to degeneration of neurites. This observation points to a potential mechanism of neuropathy development in CMT patients with NFL mutations. [5]

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. [3]

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. [4]

Furthermore, only limited human in vivo evidence is available for KE1 and its relationship to the AO.

Quantitative Understanding of the Linkage

?


Response-response Relationship

?

Time-scale

?

Known modulating factors

?

Known Feedforward/Feedback loops influencing this KER

?

Domain of Applicability

?


References

?


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.