bims-polyam 2020-10-18 papers

J Neuroinflammation. 2020 Oct 14. 17(1): 301

Ablation of polyamine catabolic enzymes provokes Purkinje cell damage, neuroinflammation, and severe ataxia.

Kamyar Zahedi, Marybeth Brooks, Sharon Barone, Negah Rahmati, Tracy Murray Stewart, Matthew Dunworth, Christina Destefano-Shields, Nupur Dasgupta, Steve Davidson, Diana M Lindquist, Christine E Fuller, Roger D Smith, John L Cleveland, Robert A Casero, Manoocher Soleimani.

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.
CONCLUSIONS: These results indicate that the disruption of polyamine catabolism, via coordinated alterations in tissue polyamine levels, elevated transglutaminase activity and increased expression, polyamination, and aggregation of α-Synuclein, leads to severe cerebellar damage and ataxia. These studies indicate that polyamine catabolism is necessary to Purkinje cell survival, and for sustaining the functional integrity of the cerebellum.

Keywords: Ataxia; Cerebellum; Gliosis; Neuroinflammation; Polyamine; Polyamine catabolism; Protein polyamination; Purkinje cells; Transglutaminase

DOI: https://doi.org/10.1186/s12974-020-01955-6

Trends Immunol. 2020 Oct 12. pii: S1471-4906(20)30214-3. [Epub ahead of print]

Polyamines and Kynurenines at the Intersection of Immune Modulation.

Elisa Proietti, Sofia Rossini, Ursula Grohmann, Giada Mondanelli.

Polyamines (i.e., putrescine, spermidine, and spermine) are bioactive polycations capable of binding nucleic acids and proteins and modulating signaling pathways. Polyamine functions have been studied most extensively in tumors, where they can promote cell transformation and proliferation. Recently, spermidine was found to exert protective effects in an experimental model of multiple sclerosis (MS) and to confer immunoregulatory properties on dendritic cells (DCs), via the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. IDO1 converts l-tryptophan into metabolites, collectively known as kynurenines, endowed with several immunoregulatory effects via activation of the arylhydrocarbon receptor (AhR). Because AhR activation increases polyamine production, the emerging scenario has identified polyamines and kynurenines as actors of an immunoregulatory circuitry with potential implications for immunotherapy in autoimmune diseases and cancer.

DOI: https://doi.org/10.1016/j.it.2020.09.007

Rev Invest Clin. 2020 May 07. 73(3):

Brain Gene Expression-DNA Methylation Correlation in Suicide Completers: Preliminary Results.

Brenda Cabrera-Mendoza, José J Martínez-Magaña, Alma D Genis-Mendoza, Nancy Monroy-Jaramillo, Consuelo Walss-Bass, Gabriel R Fries, Fernando García-Dolores, Mauro López-Armenta, Gonzalo Flores, Rubén A Vázquez-Roque, Humberto Nicolini.

BACKGROUND: Gene expression alterations have been implicated in suicide pathology. However, the study of the regulatory effect of DNA methylation on gene expression in the suicidal brain has been restricted to candidate genes.
OBJECTIVE: The objective of the study was to identify genes whose expression levels are correlated with DNA methylation in the prefrontal cortex of suicides.
METHODS: Postmortem prefrontal cortex samples from 21 suicides and six non-suicides were collected. Transcriptomic and DNA methylation profiles were evaluated with microarrays; cis correlations between gene expression and CpG methylation were screened. We then analyzed the presence of transcription factor (TF) binding sites (TFBS) at CpG sites correlated with gene expression. Gene expression of TFs involved in neurodevelopmental binding to predicted TFBS was determined in the BrainSpan database.
RESULTS: We identified 22 CpG sites whose methylation levels correlated with gene expression in the prefrontal cortex of suicides. Genes annotated to identified CpG sites were involved in neurodevelopment (BBS4, NKX6-2, AXL, CTNND1, and MBP) and polyamine metabolism (polyamine oxidase [PAOX]). Such correlations were not detected in the nonsuicide group. Nine TFs (USF1, TBP, SF1, NRF1, RFX1, SP3, PKNOX1, MAZ, and POU3F2) showed differential expression in pre- and post-natal developmental periods, according to BrainSpan database.
CONCLUSIONS: The integration of different omic technologies provided novel candidates for the investigation of genes whose expression is altered in the suicidal brain and their potential regulatory mechanisms.

DOI: https://doi.org/10.24875/RIC.19003250

Plant Physiol Biochem. 2020 Oct 12. pii: S0981-9428(20)30497-6. [Epub ahead of print]156 578-590

Treatment with spermidine alleviates the effects of concomitantly applied cold stress by modulating Ca2+, pH and ROS homeostasis, actin filament organization and cell wall deposition in pollen tubes of Camellia sinensis.

Aslıhan Çetinbaş-Genç, Giampiero Cai, Stefano Del Duca.

The aim of the current study was to examine the effect of spermidine treatment concomitant with cold stress on the elongation of Camellia sinensis pollen tube. When exogenous spermidine (0.05 mM) was applied concomitantly with cold stress, pollen germination rate and pollen tube length were significantly increased in comparison with cold stressed pollen tubes. In addition, spermidine treatment concomitantly with cold stress reduced pollen tube abnormalities induced by cold stress. Besides, cold-induced disorganizations of actin filaments were ameliorated after spermidine treatment along with cold stress because anisotropy levels of actin filaments in shank and apex of pollen tubes decreased. Changes in cold-induced callose distribution in the pollen tube cell wall were partially recovered after spermidine/cold stress treatment. Other cold-induced effects (decrease in Ca2+ content, reduction of pH gradient, accumulation of ROS) were reverted to adequate levels after spermidine treatment in conjunction with cold stress, indicating that pollen tubes are able to cope with stress. Thus, spermidine treatment reorganized the growth pattern of pollen tubes by modulating Ca2+ and ROS homeostasis, actin cytoskeleton organization, and cell wall deposition in Camellia sinensis pollen tubes under cold stress.

Keywords: Actin cytoskeleton; Cell wall; Cold stress; Pollen tube; Polyamines; Spermidine

DOI: https://doi.org/10.1016/j.plaphy.2020.10.008

Cell Biochem Biophys. 2020 Oct 11.

In Silico Prediction of Metabolic Fluxes in Cancer Cells with Altered S-adenosylmethionine Decarboxylase Activity.

Olga Dotsenko, Dmytro Shtofel.

This paper investigates the redistribution of metabolic fluxes in the cell with altered activity of S-adenosylmethionine decarboxylase (SAMdc, EC: 4.1.1.50), the key enzyme of the polyamine cycle and the common target for antitumor therapy. To address these goals, a stoichiometric metabolic model was developed that includes five metabolic pathways: polyamine, methionine, methionine salvage cycles, folic acid cycle, and the pathway of glutathione and taurine synthesis. The model is based on 51 reactions involving 57 metabolites, 31 of which are internal metabolites. All calculations were performed using the method of Flux Balance Analysis. The outcome indicates that the inactivation of SAMdc results in a significant increase in fluxes through the methionine, the taurine and glutathione synthesis, and the folate cycles. Therefore, when using therapeutic agents inactivating SAMdc, it is necessary to consider the possibility of cellular tumor metabolism reprogramming. S-adenosylmethionine affects serine methylation and activates serine-dependent de novo ATP synthesis. Methionine-depleted cell becomes methionine-dependent, searching for new sources of methionine. Inactivation of SAMdc enhances the transformation of S-adenosylmethionine to homocysteine and then to methionine. It also intensifies the transsulfuration process activating the synthesis of glutathione and taurine.

Keywords: Cancer cell; Flux balance analysis; Metabolic flux; Polyamine metabolism; S-adenosylmethionine decarboxylase; Stoichiometric model

DOI: https://doi.org/10.1007/s12013-020-00949-8