Spermine: Biological Functions & Disease-Related Research

Spermine is a polyazaalkane that is tetradecane in which the carbons at positions 1, 5, 10 and 14 are replaced by nitrogens. It has broad actions on cellular metabolism. It has a role as an antioxidant, an immunosuppressive agent and a fundamental metabolite. It is a polyazaalkane and a tetramine. Found in various tissues and organisms, it often acts as an essential growth factor in some bacterial species. Spermine is associated with nucleic acids, particularly in viruses, and is thought to stabilize the helical structure.

Spermine modulation of Alzheimer's Tau and Parkinson's α-synuclein

As the global population ages, the incidence of age-related and neurodegenerative diseases rises accordingly. Progressive neuronal dysfunction and accumulation of amyloid fibrils are the hallmark of various neurological disorders, including Alzheimer’s disease (AD), and Parkinson’s disease (PD). Of particular interest, spermine has been reported to confer neuroprotection against age-related memory decline and mitigate α-synuclein (αS)-induced neurotoxicity in animal models. Additionally, both spermidine and spermine have been found to induce autophagy, a critical process that maintains proteostasis by degrading damaged organelles and toxic protein aggregates—an essential defense against neurodegeneration. Numerous studies have demonstrated that autophagy can eliminate Tau and αS aggregates in microglia and neuronal cells, presumably with macroautophagy, a selective form of autophagy, relying on the formation of autophagosomes to sequester and degrade protein aggregates. In this study, we explore the potential of spermine as a molecular glue to regulate the conformation, condensation and ultimately degradation pathway of Tau and αS, spanning atomic-level interactions, mesoscopic LLPS behavior in vitro to functional correlates in vivo. Using time-resolved small-angle X-ray scattering (SAXS), nuclear magnetic resonance (NMR), and coarse-grained (CG) molecular dynamics simulations, we illustrate how spermine modulates the conformations of Tau and αS via electrostatic interactions. We then characterize the LLPS behaviors of Tau and αS using light microscopy, followed by in vivo studies in a C. elegans model expressing these proteins.[1]

In this study, we demonstrate that spermine promotes phase separation of both Tau and αS, leading to the formation of liquid droplets with weak intermolecular interactions. Both Tau and αS droplets exhibited dynamic liquid-like properties in vitro, as confirmed by FRAP measurements. Spermine appears to play a central stabilizing role in maintaining condensates in a liquid-like state at elevated energy levels for an extended period. This property allows subcellular systems to recognize and respond to condensates before they transition into a solid, lower-energy state. Our model suggests a dynamic interaction with cellular autophagy processes, where liquid-like condensates are recognized and cleared by autophagosomes. However, once these condensates mature into solid-like fibrils, they become resistant to autophagic fusion and clearance, contributing to the pathology seen in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. The ability of autophagosomes to target early-stage fibrils suggests a critical window that could prevent the progression of protein aggregation diseases. Overall, our data underscore the significance of spermine-induced condensates and their potential degradation via autophagy. Understanding how it modulates the intermolecular interactions of amyloidogenic proteins offers a strategy for developing therapeutic molecular glues aiming at preventing or degrading age-related aggregates.

The Potential Role of Spermine in Human Malignancies

Polyamines are small biomolecules that exist in all organisms and are crucial in many biological functions, ranging from cell growth, gene regulation, and nucleic acid stabilization to cell proliferation. Nonetheless, intracellular polyamine contents are also found to be greater in tissues or cells with high proliferation rates, for example, cancer cells, as a result of elevated polyamine biosynthesis and uptake. Numerous studies’ verdicts on polyamine content in malignant conditions have been enriched to a large extent. Among all, spermine, which is considered one of the most important polyamines produced in mammalian cells were reported to be involved in playing important roles in cell physiology, for instance, ion channel regulation, bone development, inhibition of lipid formation and involvement in the maturation of gut and immune systems. Nonetheless, spermine, as well as its derivatives, has been shown to be involved in various human cancers’ development. Numerous studies have indicated that the level of its derivatives, and the enzymes involved in spermine metabolism and catabolism pathways are associated with different malignancies.[2]

Variable polyamine profiles have been shown in various human cancers and benign diseases. Among all reported polyamines, spermine and DiAcSpm were shown to have strong clinical relevance. Aberrations of their levels in different body fluids, such as urine, plasma and tissue are reported in this review. Numerous studies have demonstrated that spermine and DiAcSpm can discriminate cancerous patients from healthy individuals. Additionally, in some cancers, spermine and DiAcSpm are able to differentiate malignancies according to different clinical stages and histological grades, demonstrating their sensitivity and specificity in cancer research. An increasing number of studies have attempted to utilize the polyamine as a target to inhibit cell progression and development, as well as coupling with commercially available drugs. Nonetheless, more laboratorial works in vitro and validations on xenograft models are required in the future before translating results into clinical treatments.

Spermine and spermidine bind CXCR4 and inhibit HIV-1 infection

Entry of the human immunodeficiency virus (HIV-1) into target cells is mediated by binding of the viral envelope glycoprotein gp120 to the CD4 receptor and a subsequent interaction with one of the two major co-receptors, CCR5 or CXCR4. HIV-1 variants using CCR5 (R5-HIV-1) predominate, while CXCR4-tropic HIV-1 (X4-HIV-1) only occurs in approximately 50% of nontreated patients, and are associated with a more rapid deterioration of the immune system. As the RP-HPLC chromatogram at 280 nm indicated a low protein/peptide content of these fractions (fig. S1A), fraction 15 was subjected to mass spectrometric analysis. This showed the predominant presence of spermine and spermidine (fig. S1, B and C), two polyamines abundantly present in semen at concentrations of up to 14 and 0.6 mM, respectively. Thin-layer chromatography (TLC) of samples derivatized with dansyl chloride  confirmed the presence of spermine, and to a lesser extent spermidine, in the X4-HIV-1 inhibitory fractions 15 to 18, while both polyamines were absent in all noninhibitory fractions. We determined the effect of synthetic spermine and spermidine on HIV-1 variants, which only differ in their V3 loop sequence determining the co-receptor tropism. The experiments were carried out with chemically defined medium and in the absence of fetal calf serum (FCS), which contains amine oxidases that convert polyamines into highly toxic intermediates. Under these conditions, both polyamines were not cytotoxic for TZM-bl and primary CD4+ T cells (fig. S3, A and B).[3]

High spermine concentrations in semen may explain restriction of X4-HIV-1 and thus selective transmission of R5 viruses in scenarios involving virus-containing semen, such as male-to-female or male-to-male transmissions. However, our findings cannot explain the apparent similar selective sexual transmission bias of R5 viruses from female to male or by other routes of infection. Thus, although the presence of a highly concentrated CXCR4 binder and selective X4-HIV-1 inhibitor most likely influences sexual transmission events involving semen, it may not be the sole determinant for bottlenecking virus transmission and other, yet to be identified, factors most likely contribute as well. Spermine and spermidine are produced in the prostate gland and play a critical role in protecting and nourishing spermatocytes. Their antioxidant and nutritional properties are crucial for maintaining the health and viability of sperm, and they contribute to the success of fertilization and reproduction.

References

[1]Sun X, Saha D, Wang X, Mörman C, Sternke-Hoffmann R, Gerez JA, Herranz-Trillo F, Riek R, Zheng W, Luo J. Spermine modulation of Alzheimer's Tau and Parkinson's α-synuclein: implications for biomolecular condensation and neurodegeneration. Nat Commun. 2025 Nov 21;16(1):10239. doi: 10.1038/s41467-025-65426-3. PMID: 41271735; PMCID: PMC12639133.

[2]Tse RT, Wong CY, Chiu PK, Ng CF. The Potential Role of Spermine and Its Acetylated Derivative in Human Malignancies. Int J Mol Sci. 2022 Jan 23;23(3):1258. doi: 10.3390/ijms23031258. PMID: 35163181; PMCID: PMC8836144.

[3]Harms M, Smith N, Han M, Groß R, von Maltitz P, Stürzel C, Ruiz-Blanco YB, Almeida-Hernández Y, Rodriguez-Alfonso A, Cathelin D, Caspar B, Tahar B, Sayettat S, Bekaddour N, Vanshylla K, Kleipass F, Wiese S, Ständker L, Klein F, Lagane B, Boonen A, Schols D, Benichou S, Sanchez-Garcia E, Herbeuval JP, Münch J. Spermine and spermidine bind CXCR4 and inhibit CXCR4- but not CCR5-tropic HIV-1 infection. Sci Adv. 2023 Jul 7;9(27):eadf8251. doi: 10.1126/sciadv.adf8251. Epub 2023 Jul 5. PMID: 37406129; PMCID: PMC10321752.