Journal
ISCIENCE
Volume 23, Issue 2, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2020.100826
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Funding
- Deutsche Forschungsgemeinschaft [JA1823/3-1, BL567/3-2]
- Cure SMA [JAB1920]
- Families of SMA [JAB0709]
- Spanish Ministry of Science and Innovation/FEDER [BFU2013-43763-P, BFU2016-78934-P]
- German Excellence Initiative
- Initiative Forschung und Therapie for SMA [JAB0709]
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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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