ATP13A2 Loss of Function-Driven Polyamine Dysregulation Induces SAM Depletion and Epigenetic Astrocyte Toxicity

polyamine biosynthesis, which diverts S-adenosyl methionine (SAM) from DNA and histone methylation, leading to increased chromatin accessibility and epigenetic reprogramming of astrocytes into a neuroinflammatory state that releases neurotoxic cytokines that promote dopaminergic neuron death. In ATP13A2 knockout mice and human models, we find that genetic and pharmacological inhibition of SAM utilization in polyamine biosynthesis prevents astrocytic epigenetic reprogramming and promotes dopaminergic neuron survival. These findings reveal a direct link between polyamine metabolism, epigenetic dysfunction, and neurotoxic inflammation, uncovering new therapeutic opportunities in Parkinson's disease.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-04-06
DOI
https://doi.org/10.64898/2026.04.02.716164
Primary Topic
Polyamine Metabolism and Applications
Type
article
Field-Weighted Citation Impact
0.00

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article

ATP13A2 Loss of Function-Driven Polyamine Dysregulation Induces SAM Depletion and Epigenetic Astrocyte Toxicity

Peter Vangheluwe, Andrea Pérez Arévalo, Aisha Sati, Joel Blanchard et al.
bioRxiv (Cold Spring Harbor Laboratory)
Polyamine Metabolism and Applications
article

ATP13A2 Loss of Function-Driven Polyamine Dysregulation Induces SAM Depletion and Epigenetic Astrocyte Toxicity

Peter Vangheluwe, Andrea Pérez Arévalo, Aisha Sati, Joel Blanchard, Tim Ahfeldt, Anna Bright, Gustavo Morrone Parfitt, Soha Sohail, Thea D Meimoun, Elena Coccia, Jennifer Strong, Sundas Ijaz, Julia Gesner
article en

Abstract

polyamine biosynthesis, which diverts S-adenosyl methionine (SAM) from DNA and histone methylation, leading to increased chromatin accessibility and epigenetic reprogramming of astrocytes into a neuroinflammatory state that releases neurotoxic cytokines that promote dopaminergic neuron death. In ATP13A2 knockout mice and human models, we find that genetic and pharmacological inhibition of SAM utilization in polyamine biosynthesis prevents astrocytic epigenetic reprogramming and promotes dopaminergic neuron survival. These findings reveal a direct link between polyamine metabolism, epigenetic dysfunction, and neurotoxic inflammation, uncovering new therapeutic opportunities in Parkinson's disease.

bioRxiv (Cold Spring Harbor Laboratory)
Allen Institute for Brain Science (US), Valid International (United Kingdom) (GB), National Hospital for Neurology and Neurosurgery (GB), Research Network (United States) (US), University College London (GB), Weizmann Institute of Science (IL), Icahn School of Medicine at Mount Sinai (US), KU Leuven (BE)
Michael J. Fox Foundation for Parkinson's Research, National Institutes of Health, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Good health and well-being
Openalex Percentile: Top 28%
Polyamine Metabolism and Applications
DOIOpen Access PDFOpenAlex
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