Abstract
Neurodegeneration can be triggered by genetic or environmental factors. Although the precise cause is often unknown, many neurodegenerative diseases share common features such as protein aggregation and age dependence. Recent studies in Drosophila have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) against activity-induced neurodegeneration and injury-induced axonal degeneration1,2. Here we show that NMNAT overexpression can also protect against spinocerebellar ataxia 1 (SCA1)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heat-shock protein 70 (Hsp70). NMNAT displays chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of poly-glutamine expanded protein and recruited with the chaperone Hsp70 into protein aggregates. Our results implicate NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection. Our studies provide an entry point for understanding how normal neurons maintain activity, and offer clues for the common mechanisms underlying different neurodegenerative conditions.
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Acknowledgements
We thank H. Zoghbi and R. Morimoto for reagents. We thank H. Zoghbi, H. Gilbert, H.-C. Lu, X. Zhou, P. Tsoulfas and A. Malhotra for technical suggestions and discussions. We also thank G. McNamara and the Analytical Imaging Core Facility at the University of Miami for imaging assistance. Some confocal imaging was supported by the BCM Mental Retardation and Developmental Disabilities Research Center. R.G.Z., P.R.H., C.M.H. were supported by the HHMI. H.J.B. is an HHMI investigator. R.G.Z. and F.Z. are also supported by the PhRMA Foundation and the Florida Department of Health, James and Esther King Biomedical Research Program.
Author Contributions R.G.Z. and H.J.B. conceived the experiments. R.G.Z., P.R.H., Y.C. and C.M.H. performed the genetic and in vivo experiments. R.G.Z. and F.Z. performed the in vitro experiments. R.G.Z. and H.J.B. wrote the manuscript.
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Zhai, R., Zhang, F., Hiesinger, P. et al. NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature 452, 887–891 (2008). https://doi.org/10.1038/nature06721
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DOI: https://doi.org/10.1038/nature06721
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