Ablation of polyamine catabolic enzymes provokes Purkinje cell damage, neuroinflammation, and severe ataxia
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(2020) 17:301
RESEARCH
Open Access
Ablation of polyamine catabolic enzymes provokes Purkinje cell damage, neuroinflammation, and severe ataxia Kamyar Zahedi1,2,3,4,5,6* , Marybeth Brooks2,3,6, Sharon Barone1,2,3,4,6, Negah Rahmati7, Tracy Murray Stewart8, Matthew Dunworth8, Christina Destefano-Shields8, Nupur Dasgupta9, Steve Davidson10, Diana M. Lindquist11, Christine E. Fuller12, Roger D. Smith13, John L. Cleveland14,15, Robert A. Casero Jr8 and Manoocher Soleimani1,2,3,4,5,6*
Abstract Background: Polyamine catabolism plays a key role in maintaining intracellular polyamine pools, yet its physiological significance is largely unexplored. Here, we report that the disruption of polyamine catabolism leads to severe cerebellar damage and ataxia, demonstrating the fundamental role of polyamine catabolism in the maintenance of cerebellar function and integrity. Methods: Mice with simultaneous deletion of the two principal polyamine catabolic enzymes, spermine oxidase and spermidine/spermine N1-acetyltransferase (Smox/Sat1-dKO), were generated by the crossbreeding of Smox-KO (Smox−/−) and Sat1-KO (Sat1−/−) animals. Development and progression of tissue injury was monitored using imaging, behavioral, and molecular analyses. Results: Smox/Sat1-dKO mice are normal at birth, but develop progressive cerebellar damage and ataxia. The cerebellar injury in Smox/Sat1-dKO mice is associated with Purkinje cell loss and gliosis, leading to neuroinflammation and white matter demyelination during the latter stages of the injury. The onset of tissue damage in Smox/Sat1-dKO mice is not solely dependent on changes in polyamine levels as cerebellar injury was highly selective. RNA-seq analysis and confirmatory studies revealed clear decreases in the expression of Purkinje cell-associated proteins and significant increases in the expression of transglutaminases and markers of neurodegenerative microgliosis and astrocytosis. Further, the α-Synuclein expression, aggregation, and polyamination levels were significantly increased in the cerebellum of Smox/Sat1-dKO mice. Finally, there were clear roles of transglutaminase-2 (TGM2) in the cerebellar pathologies manifest in Smox/Sat1-dKO mice, as pharmacological inhibition of transglutaminases reduced the severity of ataxia and cerebellar injury in Smox/ Sat1-dKO mice. (Continued on next page)
* Correspondence: [email protected]; [email protected] 1 Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creativ
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