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The Future of Research in Neuropathy

Takayuki Itoh, MD, PhD1; David Pleasure, MD1,2
[+] Author Affiliations
1Institute for Pediatric Regenerative Medicine, University of California, Davis, School of Medicine, Sacramento
2Department of Neurology, University of California, Davis, School of Medicine, c/o Shriners Hospital, Sacramento
JAMA Neurol. 2015;72(1):5-7. doi:10.1001/jamaneurol.2014.2346.
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This viewpoint focuses on the technological advances in nucleotide sequencing and genetic engineering and on our deepening understanding of the molecular processes underlying Schwann cell–axon interactions and axonal degeneration.

The future isn’t what it used to be. How will the technological advances in the analysis and modulation of gene expression, in combination with a deepening understanding of the biology of the peripheral nervous system, alter the diagnosis and management of patients with peripheral neuropathies? This review focuses on the technological advances in nucleotide sequencing and genetic engineering and on our deepening understanding of the molecular processes underlying Schwann cell–axon interactions and axonal degeneration.

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Figure.
Regulatory Pathways Leading to Axon Self-Destruction

Axonal severing disconnects the distal stump from the neuronal perikaryon, impairs axonal Ca2+ homeostasis, and activates Ca2+-dependent protein and lipid degradative enzymes. Interruption, either by transection or by inhibition of axonal transport, of the continuous supply to the distal axon of NMNAT2, a protein required for NAD+ synthesis and axon survival, is compensated for in mice expressing WldS, a mutant fusion protein consisting of the N-terminal segment of ubiquitination factor E4B (UBE4B) and the entire NMNAT1 protein, thus delaying axon destruction. The c-Jun-N-terminal kinase (JNK) pathway module, consisting of JNK, MKK4 (or MKK7), zipper protein kinase/dual leucine zipper kinase (ZPK/DLK), and the scaffold protein JIP, is also activated after axonal injury and, in contrast to WldS, accelerates axonal destruction. Also, SARM1, a member of the MyD88 adaptor protein family, dimerizes or multimerizes after axonal injury, and provides a key signal for activation of the axon self-destruction program. Interactions between these axonal survival/destruction proteins remain to be clarified, but their manipulation may provide a means for suppressing dying-back neuropathies and enhancing axonal regeneration. ATP indicates adenosine triphosphate; NAD, nicotinamide adenine dinucleotide; NMN, nicotinamide mononucleotide; TIR, Toll/interleukin-1 receptor; and VCP, valosin containing protein.

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