한빛사 논문
Tomohiro Nakamura1,2,*,†, Chang-ki Oh1,2,†, Lujian Liao1,‡, Xu Zhang1,2, Kevin M. Lopez2, Daniel Gibbs3, Amanda K. Deal1, Henry R. Scott1, Brian Spencer3, Eliezer Masliah3,§, Robert A. Rissman3,4, John R. Yates III1, Stuart A. Lipton1,2,3,*
1Departments of Molecular Medicine and Neuroscience, and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
2Neurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USA.
3Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
4VA San Diego Healthcare System, San Diego, CA 92161, USA.
*Corresponding author.
†These authors contributed equally to this work.
‡Present address: Shanghai Key Laboratory of Regulatory Biology and Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai 200241, China.
§Present address: National Institute on Aging, NIH, Bethesda, MD 20892, USA.
Abstract
Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function-transnitrosylation-that triggers a pathological biochemical cascade in mouse models and in humans with Alzheimer’s disease (AD). The resulting series of transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the postreproductive period, so natural selection against such abnormal activity may be decreased.
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