ATP13A2 loss in astrocytes depletes cytosolic polyamines, diverting SAM into de novo polyamine synthesis which drives epigenetic reprogramming to a neuroinflammatory, neuron-toxic state; genetic and pharmacologic inhibition of SAM utilization in polyamine biosynthesis prevents this reprogramming…

Reveals a targetable metabolic–epigenetic axis (polyamine biosynthesis/SAM use) linking lysosomal dysfunction to neurotoxic inflammation with demonstrated pharmacologic rescue, creating clear translational and repurposing opportunities for Parkinson's therapeutic development.

Aging is the strongest risk factor for neurodegeneration, yet how the human brain ages remains poorly understood. Loss-of-function (LOF) variants in ATP13A2 cause severe juvenile-onset Parkinson's disease, providing a window into the mechanisms that accelerate age-related neurodegeneration. ATP13A2-LOF causes lysosomal polyamine sequestration, but how this promotes pathogenesis remains unclear. We discovered that ATP13A2-LOF depletes cytosolic polyamines in astrocytes, triggering compensatory upregulation of de novo 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.