Nerve cells transmit messages along their length in the form of electrical signals. Much like an electrical wire, the nerve fiber or axon is coated by a multiple-layered insulation, called the myelin sheath.
However, unlike electrical insulation, the myelin sheath is regularly interrupted to expose short regions of the underlying nerve. These exposed regions and the adjacent regions underneath the myelin contain ion channels that help to propagate electrical signals along the axon.
Peroxisomes are compartments in animal cells that process fats. Genetic mutations that prevent peroxisomes from working properly can lead to diseases where the nerves cannot transmit signals correctly. This is thought to be because the nerves lose their myelin sheath, which largely consists of fatty molecules.
The nerves outside of the brain and spinal cord are known as peripheral nerves. Sandra Kleinecke, of the Max Planck Institute of Experimental Medicine, and colleagues, have now analyzed peripheral nerves from mice that had one of three different genetic mutations, preventing their peroxisomes from working correctly. Even in cases where the mutation severely impaired nerve signaling, the peripheral nerves retained their myelin sheath.
[caption id=“attachment_90974” align=“aligncenter” width=“700”] Hypothetical model for lipid turnover of the juxtaparanodal anchoring complex of Kv1-channels.
Myelin TAG-1 is stabilized by gangliosides (GS, light green) within juxtaparanodes (JXP).
For normal turnover (left) of JXP domains, SC require lysosomes (purple) and peroxisomes (dark green) that degrade GS (indicated by curved pink arrow).
When GS degradation is perturbed (right), indicated by impaired peroxisomes (red), GS accumulate within enlarged lysosomes (purple), storage vesicles (gray), and likely within JXP.
Excess GS within JXP stabilize the protein complex containing TAG-1 (yellow), CASPR2 (red) and Kv1.1 (blue) proteins, which thereby escape normal turnover, leading to domains breaking-off and drifting into internodes.
Extra clusters possibly allow more K+ (blue dots) efflux (curved gray arrow).
The peroxisome mutations did affect a particular type of potassium ion channel and the anchor proteins that hold these channels in place. The role of these potassium ion channels is not fully known, but normally they are only found close to regions of the axon that are not coated by myelin.
However, the peroxisome mutations meant that the channels and their protein anchors were now also located along the myelinated segments of the nerve’s axons. This redistribution of the potassium ion channels likely contributes to the peripheral nerves being unable to signal properly.
Lysosomes And Potassium Channels
In addition, the researchers found that disrupting the peroxisomes also affected another cell compartment, called the lysosome, in the nerve cells that insulate axons with myelin sheaths. Lysosomes help to break down unwanted fat molecules.
Mutant mice had more lysosomes than normal, but these lysosomes did not work efficiently. This caused the nerve cells to store more of certain types of molecules, including molecules called glycolipids that stabilize protein anchors, which hold the potassium channels in place.
A likely result is that protein anchors that would normally be degraded are not, leading to the potassium channels appearing inappropriately throughout the nerve.
Future work is now needed to investigate whether peroxisomal diseases cause similar changes in the brain. The results presented by Kleinecke et al. also suggest that targeting the lysosomes or the potassium channels could present new ways to treat disorders of the peroxisomes, such as Zellweger syndrome, infantile Refsum disease, and rhizomelic chondrodysplasia punctata.
Sandra Kleinecke, Sarah Richert, Livia de Hoz, Britta Brügger, Theresa Kungl, Ebrahim Asadollahi, Susanne Quintes, Judith Blanz, Rhona McGonigal, Kobra Naseri, Michael W Sereda, Timo Sachsenheimer, Christian Lüchtenborg, Wiebke Möbius, Hugh Willison, Myriam Baes, Klaus-Armin Nave, Celia Michèle Kassmann Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy eLife 2017;6:e23332
© 2017, Kleinecke et al. Republished under Creative Commons Attribution License. Top Image: Dr David Furness, Wellcome Images.