Mitigating aberrant Cdk5 activation alleviates mitochondrial defects and motor neuron disease symptoms in spinal muscular atrophy

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 47; p. e2300308120
• Main Authors: Miller, Nimrod, Xu, Zhaofa, Quinlan, Katharina A, Ji, Amy, McGivern, Jered V, Feng, Zhihua, Shi, Han, Ko, Chien-Ping, Tsai, Li-Huei, Heckman, Charles J, Ebert, Allison D, Ma, Yongchao C
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21.11.2023
• Subjects: Animal models; Animals; Atrophy; Biological Sciences; Cell culture; Cyclin-dependent kinase 5; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; Cyclin-dependent kinases; Defects; Degeneration; Denervation; Disease Models, Animal; Humans; Induced Pluripotent Stem Cells - metabolism; Infant mortality; Inhibitory postsynaptic potentials; Kinases; Mice; Mitochondria; Motor neuron diseases; Motor Neurons - metabolism; Muscular Atrophy, Spinal - metabolism; Nerve Degeneration - pathology; Pathogenesis; Phenotypes; Pluripotency; Signal transduction; Signs and symptoms; Spinal muscular atrophy; Stem cells; Survival of Motor Neuron 1 Protein - genetics; Survival of Motor Neuron 1 Protein - metabolism; Synapses; neurodegeneration; spinal muscular atrophy; Cdk5; mitochondria; motor neuron
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2300308120

Spinal muscular atrophy (SMA), the top genetic cause of infant mortality, is characterized by motor neuron degeneration. Mechanisms underlying SMA pathogenesis remain largely unknown. Here, we report that the activity of cyclin-dependent kinase 5 (Cdk5) and the conversion of its activating subunit p35 to the more potent activator p25 are significantly up-regulated in mouse models and human induced pluripotent stem cell (iPSC) models of SMA. The increase of Cdk5 activity occurs before the onset of SMA phenotypes, suggesting that it may be an initiator of the disease. Importantly, aberrant Cdk5 activation causes mitochondrial defects and motor neuron degeneration, as the genetic knockout of in an SMA mouse model rescues mitochondrial transport and fragmentation defects, and alleviates SMA phenotypes including motor neuron hyperexcitability, loss of excitatory synapses, neuromuscular junction denervation, and motor neuron degeneration. Inhibition of the Cdk5 signaling pathway reduces the degeneration of motor neurons derived from SMA mice and human SMA iPSCs. Altogether, our studies reveal a critical role for the aberrant activation of Cdk5 in SMA pathogenesis and suggest a potential target for therapeutic intervention.