Polyamine metabolic enzyme SAT1 remodels the neuronal transcriptome and rescues α-synuclein toxicity in Drosophila.

Authors

Zoya R Bangash, Hiroyoshi Matsui, Bedri Ranxhi, Sokol V Todi, Peter A LeWitt, Wei-Ling Tsou

Published in

Amino acids. Volume 58. Issue 1. Aug 30, 2026. Epub Aug 30, 2026.

Abstract

Polyamine homeostasis is tightly regulated by interconversion and catabolic pathways and has been increasingly implicated in neurodegenerative disorders, including Parkinson's disease (PD), where accumulation of α-synuclein (α-Syn) perturbs neuronal homeostasis. Spermidine/spermine N¹-acetyltransferase 1 (SAT1) occupies a central position in polyamine interconversion, and alterations in SAT1 activity have been linked to α-Syn toxicity and PD-related neuropathology. To investigate how SAT1 activity influences α-Syn-associated neurodegeneration, we employed a Drosophila model of neuronal α-Syn expression. SAT1 overexpression reduced α-Syn protein levels, altered its subcellular distribution within the brain, and mitigated α-Syn-induced lifespan shortening. Transcriptomic analyses showed that SAT1 modulates stress-associated gene expression in the α-Syn background, including attenuation of chaperone and ubiquitin-related responses and coordinated changes in pathways linked to mitochondrial function and amino acid metabolism. SAT1 co-expression partially restored α-Syn-associated alterations in genes involved in mitochondrial quality control, including USP30, Uch-L5R, RNF185, and the mitochondrial ornithine carrier SLC25A15. At the protein level, SAT1 increased mitochondrial-associated signal, enhanced LC3 association with mitochondrial compartments, restored LC3-II/LC3-I ratios in mitochondrial fractions, and reduced mitochondrial accumulation of α-Syn. Functional analyses further showed that SAT1 increased steady-state ATP levels and attenuated the ATP depletion induced by α-Syn expression. These findings indicate that SAT1 activity is associated with reduced α-Syn toxicity and preservation of mitochondrial homeostasis during α-Syn-associated stress.

PMID:
42734829
Bibliographic data and abstract were imported from PubMed on 15 Sep 2026.

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