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Spermidine\/spermine N\u00b9-acetyltransferase 1 (SAT1) occupies a central position in polyamine interconversion, and alterations in SAT1 activity have been linked to \u03b1-Syn toxicity and PD-related neuropathology. To investigate how SAT1 activity influences \u03b1-Syn-associated neurodegeneration, we employed a\n                    <jats:italic>Drosophila<\/jats:italic>\n                    model of neuronal \u03b1-Syn expression. SAT1 overexpression reduced \u03b1-Syn protein levels, altered its subcellular distribution within the brain, and mitigated \u03b1-Syn-induced lifespan shortening. Transcriptomic analyses showed that SAT1 modulates stress-associated gene expression in the \u03b1-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 \u03b1-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 \u03b1-Syn. Functional analyses further showed that SAT1 increased steady-state ATP levels and attenuated the ATP depletion induced by \u03b1-Syn expression. These findings indicate that SAT1 activity is associated with reduced \u03b1-Syn toxicity and preservation of mitochondrial homeostasis during \u03b1-Syn-associated stress.\n                  <\/jats:p>","DOI":"10.1007\/s00726-026-03544-y","type":"journal-article","created":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T16:14:16Z","timestamp":1788106456000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Polyamine metabolic enzyme SAT1 remodels the neuronal transcriptome and rescues \u03b1-synuclein toxicity in Drosophila"],"prefix":"10.1007","volume":"58","author":[{"given":"Zoya R.","family":"Bangash","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyoshi","family":"Matsui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2508-731X","authenticated-orcid":false,"given":"Bedri","family":"Ranxhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4399-5549","authenticated-orcid":false,"given":"Sokol V.","family":"Todi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4976-4445","authenticated-orcid":false,"given":"Peter A.","family":"LeWitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9136-2581","authenticated-orcid":false,"given":"Wei-Ling","family":"Tsou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,30]]},"reference":[{"issue":"2","key":"3544_CR1","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1007\/s00726-009-0396-7","volume":"38","author":"E Agostinelli","year":"2010","unstructured":"Agostinelli E, Marques MP, Calheiros R, Gil FP, Tempera G, Viceconte N, Battaglia V, Grancara S, Toninello A (2010) Polyamines: fundamental characters in chemistry and biology. 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