A painful neuropathy-associated Nav1.7 mutant leads to time-dependent degeneration of small-diameter axons associated with intracellular Ca2+ dysregulation and decrease in ATP levels.
Small fiber neuropathy is a painful sensory nervous system disorder characterized by damage to unmyelinated C- and thinly myelinated Aδ- nerve fibers, clinically manifested by burning pain in the distal extremities and dysautonomia. The clinical onset in adulthood suggests a time-dependent process. The mechanisms that underlie nerve fiber injury in small fiber neuropathy are incompletely understood, although roles for energetic stress have been suggested. In the present study, we report time-dependent degeneration of neurites from dorsal root ganglia neurons in culture expressing small fiber neuropathy-associated G856D mutant Nav1.7 channels and demonstrate a time-dependent increase in intracellular calcium levels [Ca2+]iand reactive oxygen species, together with a decrease in ATP levels. Together with a previous clinical report of burning pain in the feet and hands associated with reduced levels of Na+/K+-ATPase in humans with high altitude sickness, the present results link energetic stress and reactive oxygen species production with the development of a painful neuropathy that preferentially affects small-diameter axons.
Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.|Neuroscience and Regeneration Research Center, VA Connecticut Healthcare System, West Haven, CT, USA.
Harshvardhan
H
Rolyan
Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.|Neuroscience and Regeneration Research Center, VA Connecticut Healthcare System, West Haven, CT, USA.
Shujun
S
Liu
Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
Janneke Gj
JG
Hoeijmakers
Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
Catharina G
CG
Faber
Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.|Department of Neurology, St. Elisabeth Hospital, Willemstad, Curaçao.
Ingemar Sj
IS
Merkies
Neuroalgology Unit, IRCCS, Carlo Besta Neurological Institute, Milan, Italy.
Giuseppe
G
Lauria
Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.|Neuroscience and Regeneration Research Center, VA Connecticut Healthcare System, West Haven, CT, USA.
Joel A
JA
Black
Department of Neurology, Yale University School of Medicine, New Haven, CT, USA Stephen.waxman@yale.edu.|Neuroscience and Regeneration Research Center, VA Connecticut Healthcare System, West Haven, CT, USA.
Stephen G
SG
Waxman
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000473:pathology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000097573:Red Fluorescent Protein
D000255:Adenosine Triphosphate; D002118:Calcium; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D062556:NAV1.7 Voltage-Gated Sodium Channel; D017382:Reactive Oxygen Species; D000097573:Red Fluorescent Protein; C486866:SCN9A protein, human
ATP; axon degeneration; mitochondria; peripheral neuropathy; reactive oxygen species; sodium-calcium exchanger; voltage-gated sodium channel