Defective Ca2+ channel clustering in axon terminals disturbs excitability in motoneurons in spinal muscular atrophy

Abstract

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 β-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.

Regulation of SMN Protein Stability

“…PKA increases SMN complex formation and SMN stability. It has been reported that stimulation of cAMP results in increased FL-SMN levels (13,28). SMN contains three putative PKA phosphorylation sites identified by NetPhos 2.0 server (http: //www.cbs.dtu.dk/services/NetPhos) located at threonine 25, threonine 122, and serine 290 (3).…”

C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons

“…5B,C), which showed colocalization of GFP-actin with phalloidin. We performed live cell imaging with mouse motoneurons at 5 days in culture because at this stage axon extension appears with highest speed and dynamics 28 (Fig. 4A, Suppl.…”

Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

“…However, how suboptimal levels of SMN lead to SMA is largely unknown. Multiple studies in SMA mouse models revealed widespread synaptic defects in neuromuscular junctions (NMJs), including neurofilament accumulation, poor terminal arborization, immature endplates, reduced quantal content, disturbed calcium homeostasis, and decreased remodeling potential; these defects precede motor neuron death (Cifuentes-Diaz et al 2002;Le et al 2005;Jablonka et al 2007;Kariya et al 2008;Murray et al 2008Murray et al , 2012Kong et al 2009;Ling et al 2010;Ruiz et al 2010;Lee et al 2011), suggesting that the NMJ alterations are the initial consequence of SMN deficiency, Ó 2015 Hua et al This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http:// creativecommons.org/licenses/by-nc/4.0/.…”