Aberrant AZIN2 and Polyamine Metabolism Precipitates Tau Neuropathology

Authors

Leslie A. Sandusky-Beltran, University of South Florida
Andrii Kovalenko, University of South Florida
Devon S. Placides, University of South Florida
Kevin Ratnasamy, University of South Florida
Chao Ma, University of Kentucky
Jerry B. Hunt, University of KentuckyFollow
Huimin Liang, University of KentuckyFollow
John Ivan T. Calahatian, University of South Florida
Camilla Michalski, McMaster University, Canada
Margaret Fahnestock, McMaster University, Canada
Laura J. Blair, University of South Florida
April L. Darling, University of South Florida
Jeremy D. Baker, University of South Florida
Sarah N. Fontaine, University of South Florida
Chad A. Dickey, University of South Florida
Joshua J. Gamsby, University of South Florida
Kevin R. Nash, University of South Florida
Erin L. Abner, University of KentuckyFollow
Maj-Linda B. Selenica, University of KentuckyFollow
Daniel C. Lee, University of KentuckyFollow

Abstract

Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell’s response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer’s disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD.

Document Type

Article

Publication Date

2-15-2021

Notes/Citation Information

Published in The Journal of Clinical Investigation, v. 131, issue 4.

© 2021 American Society for Clinical Investigation

The copyright holder has granted the permission for posting the article here.

Digital Object Identifier (DOI)

https://doi.org/10.1172/jci126299

Funding Information

This work was supported by grants from the Alzheimer’s Association (MNIRGD-12-242665 to DCL), Brightfocus Foundation (A20155045 to DCL), CurePSP, Inc. (520-14 to DCL), Florida Department of Health (5AZ11 to DCL), and NIH R01AG054559 (to DCL).

Repository Citation

Sandusky-Beltran, Leslie A.; Kovalenko, Andrii; Placides, Devon S.; Ratnasamy, Kevin; Ma, Chao; Hunt, Jerry B.; Liang, Huimin; Calahatian, John Ivan T.; Michalski, Camilla; Fahnestock, Margaret; Blair, Laura J.; Darling, April L.; Baker, Jeremy D.; Fontaine, Sarah N.; Dickey, Chad A.; Gamsby, Joshua J.; Nash, Kevin R.; Abner, Erin L.; Selenica, Maj-Linda B.; and Lee, Daniel C., "Aberrant AZIN2 and Polyamine Metabolism Precipitates Tau Neuropathology" (2021). Sanders-Brown Center on Aging Faculty Publications. 170.
https://uknowledge.uky.edu/sbcoa_facpub/170