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

Rocio Tejero; Stefanie Balk; Julio Franco-Espin; Jorge Ojeda; Luisa Hennlein; Hans Drexl; Benjamin Dombert; Jan-Dierk Clausen; Laura Torres-Benito; Lena Saal-Bauernschubert; Robert Blum; Michael Briese; Silke Appenzeller; Lucia Tabares; Sibylle Jablonka

doi:10.1016/j.isci.2020.100826

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

iScience. 2020 Feb 21;23(2):100826. doi: 10.1016/j.isci.2020.100826. Epub 2020 Jan 10.

Authors

Affiliations

¹ Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain.
² Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany.
³ Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080 Würzburg, Germany; Core Unit SysMed, University of Würzburg, 97080 Würzburg, Germany.
⁴ Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain. Electronic address: ltabares@us.es.
⁵ Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany. Electronic address: jablonka_s@ukw.de.

Abstract

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 Ca_v2.1/Ca_v2.2 channel modifier and a cyclin-dependent kinase 5 (Cdk-5) inhibitor, significantly improved survival of SMA mice. In addition, R-Roscovitine increased Ca_v2.1 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 Ca_v2.2 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.

Keywords: Cellular Neuroscience; Clinical Neuroscience; Neuroscience.