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Cover ArticleArticles, Neurobiology of Disease

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 and Yong-Chao Ma
Journal of Neuroscience 15 April 2015, 35 (15) 6038-6050; DOI: https://doi.org/10.1523/JNEUROSCI.3716-14.2015
Nimrod Miller
1Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611,
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Zhihua Feng
2Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089,
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Brittany M. Edens
1Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611,
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Ben Yang
1Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611,
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Han Shi
1Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611,
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Christie C. Sze
1Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611,
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Benjamin Taige Hong
1Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611,
3State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China,
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Susan C. Su
4Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and
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Jorge A. Cantu
1Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611,
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Jacek Topczewski
1Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611,
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Thomas O. Crawford
5Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Chien-Ping Ko
2Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089,
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Charlotte J. Sumner
5Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Long Ma
3State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China,
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Yong-Chao Ma
1Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Lurie Children's Hospital of Chicago, Chicago, Illinois 60611,
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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 of tau 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.

  • Cdk5
  • motor neuron
  • neurodegeneration
  • SMA
  • tau
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The Journal of Neuroscience: 35 (15)
Journal of Neuroscience
Vol. 35, Issue 15
15 Apr 2015
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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
Journal of Neuroscience 15 April 2015, 35 (15) 6038-6050; DOI: 10.1523/JNEUROSCI.3716-14.2015

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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
Journal of Neuroscience 15 April 2015, 35 (15) 6038-6050; DOI: 10.1523/JNEUROSCI.3716-14.2015
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Keywords

  • CDK5
  • motor neuron
  • neurodegeneration
  • SMA
  • tau

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