2. Academic Validation
  3. Tau modification by the norepinephrine metabolite DOPEGAL stimulates its pathology and propagation

Tau modification by the norepinephrine metabolite DOPEGAL stimulates its pathology and propagation

  • Nat Struct Mol Biol. 2022 Apr;29(4):292-305. doi: 10.1038/s41594-022-00745-3.
Seong Su Kang 1,  Lanxia Meng 2,  Xingyu Zhang 2,  Zhiping Wu 3 4,  Ariana Mancieri 3 4,  Boer Xie 3 4,  Xia Liu 1,  David Weinshenker 5,  Junmin Peng 3 4,  Zhentao Zhang 6,  Keqiang Ye 7 8 9
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
  • 2 Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
  • 3 Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 4 Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 5 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
  • 6 Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China. [email protected].
  • 7 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. [email protected].
  • 8 Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Shenzhen, China. [email protected].
  • 9 The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Shenzhen, China. [email protected].
PMID: 35332321 DOI: 10.1038/s41594-022-00745-3
Abstract

The noradrenergic locus ceruleus (LC) is the first site of detectable tau pathology in Alzheimer's disease (AD), but the mechanisms underlying the selective vulnerability of the LC in AD have not been completely identified. In the present study, we show that DOPEGAL, a Monoamine Oxidase A (MAO-A) metabolite of norepinephrine (NE), reacts directly with the primary amine on the Lys353 residue of tau to stimulate its aggregation and facilitate its propagation. Inhibition of MAO-A or mutation of the Lys353 residue to arginine (Lys353Arg) decreases tau Lys353-DOPEGAL levels and diminishes tau pathology spreading. Wild-type tau preformed fibrils (PFFs) trigger Lys353-DOPEGAL formation, tau pathology propagation and cognitive impairment in MAPT transgenic mice, all of which are attenuated with PFFs made from the Lys353Arg mutant. Thus, the selective vulnerability of LC neurons in AD may be explained, in part, by NE oxidation via MAO-A into DOPEGAL, which covalently modifies tau and accelerates its aggregation, toxicity and propagation.

Figures
Products