Akinesia and freezing caused by Na+ leak-current channel (NALCN) deficiency corrected by pharmacological inhibition of K+ channels and gap junctions.

The Na+ leak-current channel (NALCN) regulates locomotion, respiration, and intellectual development. Previous work highlighted striking similarities between characteristic movement phenotypes of NALCN-deficient animals (Drosophila and Caenorhabditis elegans) and the major symptoms of Parkinson's disease and primary progressive freezing gait. We have discovered novel physiological connections between the NALCN, K+ channels, and gap junctions that mediate regulation of locomotion in C. elegans. Drugs that block K+ channels and gap junctions or that activate Ca++ channels significantly improve movement of NALCN-deficient animals. Loss-of-function of the NALCN creates an imbalance in ions, including K+ and Ca++ , that interferes with normal cycles of depolarization-repolarization. This work suggests new therapeutic strategies for certain human movement disorders. J. Comp. Neurol. 525:1109-1121, 2017.