Spermine modulation of Alzheimer’s Tau and Parkinson’s α-synuclein: implications for biomolecular condensation and neurodegeneration

Xun Sun, Debasis Saha, Xue Wang, Cecilia Mörman, Rebecca Sternke-Hoffmann, Juan Atilio Gerez, Fátima Herranz-Trillo, Roland Riek, Wenwei Zheng and Jinghui Luo ()
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Xun Sun: Paul Scherrer Institute, Center for Life Sciences
Debasis Saha: Arizona State University, College of Integrative Sciences and Arts
Xue Wang: Paul Scherrer Institute, Center for Life Sciences
Cecilia Mörman: Paul Scherrer Institute, Center for Life Sciences
Rebecca Sternke-Hoffmann: Paul Scherrer Institute, Center for Life Sciences
Juan Atilio Gerez: ETH Zurich, Institute of Molecular Physical Science, Department of Chemistry and Applied Biosciences
Fátima Herranz-Trillo: MAX IV Laboratory, CoSAXS Beamline
Roland Riek: ETH Zurich, Institute of Molecular Physical Science, Department of Chemistry and Applied Biosciences
Wenwei Zheng: Arizona State University, College of Integrative Sciences and Arts
Jinghui Luo: Paul Scherrer Institute, Center for Life Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Spermine, a pivotal player in biomolecular condensation and diverse cellular processes, has emerged as a focus of investigation in aging, neurodegeneration, and other diseases. Despite its significance, the mechanistic details of spermine remain incompletely understood. Here, we describe the distinct modulation by spermine on Alzheimer’s Tau and Parkinson’s α-synuclein, elucidating their condensation behaviors in vitro and in vivo. Using biophysical techniques including time-resolved SAXS and NMR, we trace electrostatically driven transitions from atomic-scale conformational changes to mesoscopic structures. Notably, spermine extends lifespan, ameliorates movement deficits, and restores mitochondrial function in C. elegans models expressing Tau and α-synuclein. Acting as a molecular glue, spermine orchestrates in vivo condensation of α-synuclein, influences condensate mobility, and promotes degradation via autophagy, specifically through autophagosome expansion. This study unveils the interplay between spermine, protein condensation, and functional outcomes, advancing our understanding of neurodegenerative diseases and paving the way for therapeutic development.

Date: 2025
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DOI: 10.1038/s41467-025-65426-3

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