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
Affiliations
Rocio Tejero
Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain
Stefanie Balk
Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany
Julio Franco-Espin
Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain
Jorge Ojeda
Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain
Luisa Hennlein
Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany
Hans Drexl
Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany
Benjamin Dombert
Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany
Jan-Dierk Clausen
Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany
Laura Torres-Benito
Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain
Lena Saal-Bauernschubert
Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany
Robert Blum
Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany
Michael Briese
Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany
Silke Appenzeller
Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, 97080 Würzburg, Germany; Core Unit SysMed, University of Würzburg, 97080 Würzburg, Germany
Lucia Tabares
Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain; Corresponding author
Sibylle Jablonka
Institute of Clinical Neurobiology, University Hospital Würzburg, 97078 Würzburg, Germany; Corresponding author
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. : Neuroscience; Clinical Neuroscience; Cellular Neuroscience Subject Areas: Neuroscience, Clinical Neuroscience, Cellular Neuroscience
