Muscle and motor neuron disorders

Publication date: 17/11/2023

Authors: Miller, N., Xu, Z., Quinlan, K.A., et al.

Journal: Proc Natl Acad Sci U S A (PNAS), 120(47):e2300308120

Commentary: The following article presents a potential strategy for the treatment of Spinal Muscular Atrophy (SMA), the leading genetic cause of infant mortality characterized by motor neuron degeneration, although its pathogenic mechanisms are not well understood. This study shows that cyclin-dependent kinase 5 (Cdk5) is abnormally activated in both mouse and human induced pluripotent stem cell (iPSC) models of SMA before symptoms appear. By genetically reducing Cdk5 activity in an SMA mouse model, the researchers corrected mitochondrial defects and significantly alleviated disease symptoms such as motor neuron degeneration, hyperexcitability, loss of excitatory synapses and denervation of neuromuscular junctions. The results point to a new pathogenic mechanism involving the upregulation of Cdk5 activity. Furthermore, the study shows that inhibition of Cdk5 signaling reduces motor neuron degeneration in SMA models. This suggests that targeting abnormal Cdk5 activation could improve the symptoms of SMA and benefit patients. Therefore, this research is significant as it identifies a new therapeutic target for SMA. Indeed, targeting Cdk5 could complement existing therapies and provide hope for better outcomes in SMA patients by preventing motor neuron degeneration and improving mitochondrial function.

Commented by: Anna Caretto (20/03/2025)

DOI: 10.1073/pnas.2300308120