Potassium channel abnormalities are consistent with early axon degeneration of motor axons in the G127X SOD1 mouse model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease, which selectively affects upper and lower motoneurones. The underlying pathophysiology of the disease is complex but electrophysiological studies of peripheral nerves in ALS patients as well as human autopsy studies indicate that a potassium channel dysfunction/loss is present early in the symptomatic phase. It remains unclear to what extent potassium channel abnormalities reflect a specific pathogenic mechanism in ALS. The aim of this study was therefore to investigate the temporal changes in the expression and/or function of potassium channels in motoneurones in the adult G127X SOD1 mouse model of ALS, a model which has a very long presymptomatic phase. Evidence from animal models indicates that the early progressive motoneurone dysfunction and degeneration can be largely compensated by motor unit remodeling, delaying the clinical symptom onset. Experiments were therefore performed both before and after symptom onset. Immunohistochemistry of motor axons in the ventral roots of G127X SOD1 mice, was used to investigate juxta-paranodal Kv1.2 potassium channels along with nodal Nav1.6 and the paranodal scaffolding protein Caspr. This allowed an investigation of changes in the distribution of Kv1.2 relative to the general structure of the nodal-paranodal-juxta-paranodal complex. This revealed that the motor axons in the ventral roots of presymptomatic G127X SOD1 mice, already show a disruption in juxta-paranodal Kv1.2 potassium channels. The axonal Kv1.2 disruption was preceded by abnormalities in the distribution of the paranodal scaffolding protein Caspr with the nodal arrangement of Nav1.6 appearing relatively preserved even in symptomatic mice. These changes were accompanied by axon swelling and a slowing of conduction in the peripheral motor axons in symptomatic mice. In vivo electrophysiological intracellular recordings of individual spinal motoneurones revealed that central potassium channel function was preserved or even enhanced with higher amplitude and longer duration after-hyperpolarisations in the G127X SOD1 mice. Our data suggest that the potassium channel abnormalities observed in presymptomatic G127X, rather than representing a specific pathophysiological mechanism targeting potassium channels, most likely reflect early axonal degenerative changes, consistent with the "dying-back" phenomenon observed in other ALS models.
Centre for Neuroscience, Copenhagen University, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
Rikke
R
Maglemose
Centre for Neuroscience, Copenhagen University, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
Anne
A
Hedegaard
Centre for Neuroscience, Copenhagen University, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
Janna
J
Lehnhoff
Centre for Neuroscience, Copenhagen University, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
Kristina Petrova
KP
Dimintiyanova
Centre for Neuroscience, Copenhagen University, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
Mihai
M
Moldovan
Centre for Neuroscience, Copenhagen University, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
Lillian
L
Grøndahl
Centre for Neuroscience, Copenhagen University, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. Electronic address: claire@sund.ku.dk.
Claire Francesca
CF
Meehan
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D010525:Peripheral Nerves / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D013126:Spinal Nerve Roots / Q000378:metabolism* / Q000473:pathology
D015221:Potassium Channels
Amyotrophic lateral sclerosis; Degeneration; Motoneurons; Potassium channels