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

## TL;DR

The enzyme SAT1 reduces α-synuclein toxicity in fruit flies by altering gene activity and improving mitochondrial health.

## Contribution

This study reveals SAT1's novel role in mitigating α-synuclein toxicity through transcriptomic and mitochondrial proteostasis changes.

## Key findings

- SAT1 overexpression reduces α-synuclein levels and alters its brain distribution in Drosophila.
- SAT1 modulates stress-related gene expression and mitochondrial pathways in α-synuclein models.
- SAT1 improves mitochondrial proteostasis by enhancing LC3 association and reducing α-synuclein accumulation.

## 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 attenuated 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. Our findings indicate that SAT1 activity is associated with reduced α-Syn toxicity and altered mitochondrial-associated proteostasis during α-Syn expression.