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

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


Neurotransmission defects and motoneuron degeneration are hallmarks of spina/ 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(v)2.1/Ca(v)2.2 channel modifier and a cyclin-dependent kinase 5 (Cdk-5) inhibitor, significantly improved survival of SMA mice. In addition, R-Roscovitine increased Cay2.1 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(v)2.2 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.

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Título según WOS: ID WOS:000518637100053 Not found in local WOS DB
Título de la Revista: ISCIENCE
Volumen: 23
Número: 2
Editorial: Cell Press
Fecha de publicación: 2020


Notas: ISI