Journal of Molecular Neuroscience

, Volume 56, Issue 4, pp 966–976 | Cite as

Death Receptor 6 and Caspase-6 Regulate Prion Peptide-Induced Axonal Degeneration in Rat Spinal Neurons

  • Yunsheng Wang
  • Deming Zhao
  • Bo Pan
  • Zhiqi Song
  • Syed Zahid Ali Shah
  • Xiaomin Yin
  • Xiangmei Zhou
  • Lifeng YangEmail author


Axonal degeneration is a hallmark of many neurodegenerative disorders including transmissible spongiform encephalopathies (TSE). However, the full complement of axonal degeneration triggers is not fully understood. In an in vitro prion model, we observed that treatment of rat spinal neurons with the prion peptide, PrP106-126, activated death receptor 6 (DR6, also known as TNFRSF21), caspase-6, caspase-3, and induced axonal degeneration. Knockdown of DR6 by siRNA blocked caspase-6 and caspase-3 activation and axonal degeneration. We also found that cleaved caspase-3 is only enriched in cell bodies, but cleaved caspase-6 is expressed in both cell bodies and axons. Axonal degeneration was prevented by preincubation of neurons with a caspase-6 inhibitor or siRNA of caspase-6. Our findings suggest that both DR6 and caspase-6 play important roles in axonal degeneration and caspase-6 acts downstream of DR6. We also observed that nicotinamide nucleotide adenylyltransferase 1 protein (Nmnat1), which had been reported to protect neurons from degeneration, alleviated axonal degeneration without blocking caspase-6 activation, suggesting that Nmnat acts downstream or parallel to caspase-6 activation. Our results indicate that PrP106-126 triggered axonal degeneration of the spinal cord neurons, DR6 is a key regulator of axonal degeneration, and the signaling pathway of DR6/caspase-6 mediates axonal degeneration induced by the prion fragment. Our findings raise the hope of targeting the DR6 as a potential therapeutic strategy in prion-related neurodegenerative diseases.


PrP106-126 Axonal degeneration Death receptor 6 Caspase-6 



This work was supported by the Natural Science Foundation of China (Project No. 31272532 and No. 31172293), the Ministry of Agriculture Program of China (No. 2013-S11 and No. 2014-S9), and the Program for Cheung Kong Scholars and Innovative Research Team in the University of China (No. IRT0866).


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yunsheng Wang
    • 1
  • Deming Zhao
    • 1
  • Bo Pan
    • 1
  • Zhiqi Song
    • 1
  • Syed Zahid Ali Shah
    • 1
  • Xiaomin Yin
    • 1
  • Xiangmei Zhou
    • 1
  • Lifeng Yang
    • 1
    Email author
  1. 1.State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary MedicineChina Agricultural UniversityBeijingChina

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