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

Authors: Wang, Yunsheng  Zhao, Deming  Pan, Bo  Song, Zhiqi  Shah, Syed Zahid Ali  Yin, Xiaomin  Zhou, Xiangmei  Yang, Lifeng 
Citation: Wang Y, etal., J Mol Neurosci. 2015 Aug;56(4):966-976. doi: 10.1007/s12031-015-0562-1. Epub 2015 Apr 22.
Pubmed: (View Article at PubMed) PMID:25898930
DOI: Full-text: DOI:10.1007/s12031-015-0562-1

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.

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CRRD Object Information
CRRD ID: 13781947
Created: 2018-08-14
Species: All species
Last Modified: 2018-08-14
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.