R-Roscovitine Improves Motoneuron Function in Mouse Models for Spinal Muscular Atrophy

Neurotransmission defects and motoneuron degeneration are hallmarks of spinal muscular atrophy, a monogenetic disease caused by the deficiency of the SMN protein. In the present study, we show that systemic application of R-Roscovitine, a Cav2.1/Cav2.2 channel modifier and a cyclin-dependent kinase...

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Published iniScience Vol. 23; no. 2; p. 100826
Main Authors Tejero, Rocio, Balk, Stefanie, Franco-Espin, Julio, Ojeda, Jorge, Hennlein, Luisa, Drexl, Hans, Dombert, Benjamin, Clausen, Jan-Dierk, Torres-Benito, Laura, Saal-Bauernschubert, Lena, Blum, Robert, Briese, Michael, Appenzeller, Silke, Tabares, Lucia, Jablonka, Sibylle
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 21.02.2020
Elsevier
Subjects
Cellular Neuroscience
Clinical Neuroscience
Neuroscience
Neuroscience
Cellular Neuroscience
Clinical Neuroscience
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Summary:Neurotransmission defects and motoneuron degeneration are hallmarks of spinal muscular atrophy, a monogenetic disease caused by the deficiency of the SMN protein. In the present study, we show that systemic application of R-Roscovitine, a Cav2.1/Cav2.2 channel modifier and a cyclin-dependent kinase 5 (Cdk-5) inhibitor, significantly improved survival of SMA mice. In addition, R-Roscovitine increased Cav2.1 channel density and sizes of the motor endplates. In vitro, R-Roscovitine restored axon lengths and growth cone sizes of Smn-deficient motoneurons corresponding to enhanced spontaneous Ca2+ influx and elevated Cav2.2 channel cluster formations independent of its capability to inhibit Cdk-5. Acute application of R-Roscovitine at the neuromuscular junction significantly increased evoked neurotransmitter release, increased the frequency of spontaneous miniature potentials, and lowered the activation threshold of silent terminals. These data indicate that R-Roscovitine improves Ca2+ signaling and Ca2+ homeostasis in Smn-deficient motoneurons, which is generally crucial for motoneuron differentiation, maturation, and function. [Display omitted] •R-Roscovitine prolongs survival of SMA mice•R-Roscovitine increases Ca2+ influx and growth cone size of SMA motoneurons•R-Roscovitine beneficially affects neurotransmission in SMA motor nerve terminals•R-Roscovitine wakes up dormant synapses of SMA motoneurons Neuroscience; Clinical Neuroscience; Cellular Neuroscience
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These authors contributed equally
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2020.100826