Defective Ca2+ channel clustering in axon terminals disturbs excitability in motoneurons in spinal muscular atrophy.
Proximal spinal muscular atrophy (SMA) is a motoneuron disease for which there is currently no effective treatment. In animal models of SMA, spinal motoneurons exhibit reduced axon elongation and growth cone size. These defects correlate with reduced beta-actin messenger RNA and protein levels in distal axons. We show that survival motoneuron gene (Smn)-deficient motoneurons exhibit severe defects in clustering Cav2.2 channels in axonal growth cones. These defects also correlate with a reduced frequency of local Ca2+ transients. In contrast, global spontaneous excitability measured in cell bodies and proximal axons is not reduced. Stimulation of Smn production from the transgenic SMN2 gene by cyclic adenosine monophosphate restores Cav2.2 accumulation and excitability. This may lead to the development of new therapies for SMA that are not focused on enhancing motoneuron survival but instead investigate restoration of growth cone excitability and function.
Jablonka
Sibylle
S
Institute for Clinical Neurobiology, University of Wuerzburg, Wuerzburg D-97078, Germany.
Beck
Marcus
M
Lechner
Barbara Dorothea
BD
Mayer
Christine
C
Sendtner
Michael
M
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D049108:Cell Enlargement / Q000187:drug effects; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D020439:Growth Cones / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D007797:Laminin / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics; D055532:SMN Complex Proteins; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology; D013873:Thionucleotides / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; D007797:Laminin; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D013873:Thionucleotides; D020960:omega-Conotoxins; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; C078452:ziconotide; D000242:Cyclic AMP