eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction

Liang, YongTian; Piao, Chengji; Beuschel, Christine B.; Toppe, David; Kollipara, Laxmikanth; Bogdanow, Boris; Maglione, Marta; Lützkendorf, Janine; See, Jason Chun Kit; Huang, Sheng; Conrad, Tim; Kintscher, Ulrich; Madeo, Frank; Liu, Fan; Sickmann, Albert; Sigrist, Stephan J.

doi:10.1016/j.celrep.2021.108941

Cited by 78 publications

(76 citation statements)

References 63 publications

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“…In this work, we analyzed four aminosterols, squalamine (SQ), des-squalamine (desSQ), α-squalamine (αSQ), and trodusquemine (TRO), with slightly different physicochemical properties (Figure 1). The investigation of the addition of polyamine groups to a sterol moiety is particularly interesting following recent reports about the remarkable ability of polyamines to modulate cellular homeostasis (Schroeder et al, 2021;Liang et al, 2021). TRO contains a spermine moiety as its polyamine side chain, while SQ and its derivatives have a spermidine linked to the fused sterol ring.…”

Section: Resultsmentioning

confidence: 99%

Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers

et al. 2021

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The aberrant aggregation of proteins is a key molecular event in the development and progression of a wide range of neurodegenerative disorders. We have shown previously that squalamine and trodusquemine, two natural products in the aminosterol class, can modulate the aggregation of the amyloid-β peptide (Aβ) and of α-synuclein (αS), which are associated with Alzheimer’s and Parkinson’s diseases. In this work, we expand our previous analyses to two squalamine derivatives, des-squalamine and α-squalamine, obtaining further insights into the mechanism by which aminosterols modulate Aβ and αS aggregation. We then characterize the ability of these small molecules to alter the physicochemical properties of stabilized oligomeric species in vitro and to suppress the toxicity of these aggregates to varying degrees toward human neuroblastoma cells. We found that, despite the fact that these aminosterols exert opposing effects on Aβ and αS aggregation under the conditions that we tested, the modifications that they induced to the toxicity of oligomers were similar. Our results indicate that the suppression of toxicity is mediated by the displacement of toxic oligomeric species from cellular membranes by the aminosterols. This study, thus, provides evidence that aminosterols could be rationally optimized in drug discovery programs to target oligomer toxicity in Alzheimer’s and Parkinson’s diseases.

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Section: Resultsmentioning

confidence: 99%

Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers

et al. 2021

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“…In addition to the highlighted major pathways, recent studies have identified translational control through eIF5A hypusination apparent in cellular ageing. eIF5A is an elongation factor that contains a unique amino acid hypusine, synthesised by a transfer of the aminobutyl moiety from spermidine (a polyamine) to lysine 50 (human) of eIF5A [ 128 , 129 ]. Hypusinated eIF5A can alleviate ribosome stalling in ‘hard-to-translate’ mRNA motifs, including polyproline tracts [ 129 , 130 ].…”

Section: Future Research Directions and Areas Of Interestmentioning

confidence: 99%

“…Because in ageing levels of spermidine decrease, hypusinated eIF5A becomes less available, and the autophagy is suppressed [ 131 , 132 ]. It is noteworthy, that a mere supplementation of spermidine in aged Drosophila brains has improved mitochondrial function and memory [ 128 ]. In aged mice, spermidine supplementation improved B-cell responses [ 131 ].…”

Section: Future Research Directions and Areas Of Interestmentioning

confidence: 99%

Translational control in cell ageing: an update

Woodward

Shirokikh

2021

Biochemical Society Transactions

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Cellular ageing is one of the main drivers of organismal ageing and holds keys towards improving the longevity and quality of the extended life. Elucidating mechanisms underlying the emergence of the aged cells as well as their altered responses to the environment will help understanding the evolutionarily defined longevity preferences across species with different strategies of survival. Much is understood about the role of alterations in the DNA, including many epigenetic modifications such as methylation, in relation to the aged cell phenotype. While transcriptomes of the aged cells are beginning to be better-characterised, their translational responses remain under active investigation. Many of the translationally controlled homeostatic pathways are centred around mitigation of DNA damage, cell stress response and regulation of the proliferative potential of the cells, and thus are critical for the aged cell function. Translation profiling-type studies have boosted the opportunities in discovering the function of protein biosynthesis control and are starting to be applied to the aged cells. Here, we provide a summary of the current knowledge about translational mechanisms considered to be commonly altered in the aged cells, including the integrated stress response-, mechanistic target of Rapamycin- and elongation factor 2 kinase-mediated pathways. We enlist and discuss findings of the recent works that use broad profiling-type approaches to investigate the age-related translational pathways. We outline the limitations of the methods and the remaining unknowns in the established ageing-associated translation mechanisms, and flag translational mechanisms with high prospective importance in ageing, for future studies.

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“…Simple feeding with spermidine not only restored the juvenile polyamine level, but also suppressed age-related memory disorders and preserved the ability to move [ 135 ]. In addition, efficient hypusination has been shown to be decisive for the protection of spermidine-mediated mitochondrial functionality [ 136 ]. The results obtained with the central nervous system of Drosophila provide evidence that spermidine promotes mitochondrial respiration in the course of brain aging and that brain eIF5A hypusination declines with aging (Fig.…”

Section: Brain Aging and Neural Developmentmentioning

confidence: 99%

“…In addition, the weakening of eIF5A hypusination significantly influenced mitochondrial functionality and the protein composition in Drosophila [ 136 ] but also in mammals [ 84 , 137 ]. Inhibition of eIF5A hypusination nullified a spectrum of age-related effects of spermidine on mitochondrial functionality, locomotion, and memory.…”

Section: Brain Aging and Neural Developmentmentioning

confidence: 99%

The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles

et al. 2021

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Since the demonstration of its involvement in cell proliferation, the eukaryotic initiation factor 5A (eIF5A) has been studied principally in relation to the development and progression of cancers in which the isoform A2 is mainly expressed. However, an increasing number of studies report that the isoform A1, which is ubiquitously expressed in normal cells, exhibits novel molecular features that reveal its new relationships between cellular functions and organ homeostasis. At a first glance, eIF5A can be regarded, among other things, as a factor implicated in the initiation of translation. Nevertheless, at least three specificities: (1) its extreme conservation between species, including plants, throughout evolution, (2) its very special and unique post-translational modification through the activating-hypusination process, and finally (3) its close relationship with the polyamine pathway, suggest that the role of eIF5A in living beings remains to be uncovered. In fact, and beyond its involvement in facilitating the translation of proteins containing polyproline residues, eIF5A is implicated in various physiological processes including ischemic tolerance, metabolic adaptation, aging, development, and immune cell differentiation. These newly discovered physiological properties open up huge opportunities in the clinic for pathologies such as, for example, the ones in which the oxygen supply is disrupted. In this latter case, organ transplantation, myocardial infarction or stroke are concerned, and the current literature defines eIF5A as a new drug target with a high level of potential benefit for patients with these diseases or injuries. Moreover, the recent use of genomic and transcriptomic association along with metadata studies also revealed the implication of eIF5A in genetic diseases. Thus, this review provides an overview of eIF5A from its molecular mechanism of action to its physiological roles and the clinical possibilities that have been recently reported in the literature.

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eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction

Cited by 78 publications

References 63 publications

Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers

Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers

Translational control in cell ageing: an update

The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles

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