التفاصيل البيبلوغرافية
| العنوان: |
Mitigating aberrant Cdk5 activation alleviates mitochondrial defects and motor neuron disease symptoms in spinal muscular atrophy. |
| المؤلفون: |
Miller, Nimrod, Zhaofa Xu, Quinlan, Katharina A., Amy Ji, McGivern, Jered V., Zhihua Feng, Han Shi, Chien-Ping Ko, Li-Hue, Heckman, Charles J., Ebert, Allison D., Ma, Yongchao C. |
| المصدر: |
Proceedings of the National Academy of Sciences of the United States of America; 11/21/2023, Vol. 120 Issue 47, p1-12, 16p |
| مصطلحات موضوعية: |
MOTOR neuron diseases, SPINAL muscular atrophy, SYMPTOMS, INDUCED pluripotent stem cells, MOTOR neurons |
| مستخلص: |
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 p35 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. [ABSTRACT FROM AUTHOR] |
|
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
