Non-aggregating tau phosphorylation by cyclin-dependent kinase 5 contributes to motor neuron degeneration in spinal muscular atrophy

Nimrod Miller, Zhihua Feng, Brittany M. Edens, Ben Yang, Han Shi, Christie C. Sze, Benjamin Taige Hong, Susan C. Su, Jorge A. Cantu, Jacek Topczewski, Thomas O. Crawford, Chien Ping Ko, Charlotte J. Sumner, Long Ma, Yong Chao Ma

Research output: Contribution to journalArticle

Abstract

Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35−/− compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out oftau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration.

Original languageEnglish (US)
Pages (from-to)6038-6050
Number of pages13
JournalJournal of Neuroscience
Volume35
Issue number15
DOIs
StatePublished - Apr 15 2015

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Keywords

  • Cdk5
  • Motor neuron
  • Neurodegeneration
  • SMA
  • Tau

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Miller, N., Feng, Z., Edens, B. M., Yang, B., Shi, H., Sze, C. C., Hong, B. T., Su, S. C., Cantu, J. A., Topczewski, J., Crawford, T. O., Ko, C. P., Sumner, C. J., Ma, L., & Ma, Y. C. (2015). Non-aggregating tau phosphorylation by cyclin-dependent kinase 5 contributes to motor neuron degeneration in spinal muscular atrophy. Journal of Neuroscience, 35(15), 6038-6050. https://doi.org/10.1523/JNEUROSCI.3716-14.2015