Biology subjects

Bright, A.

Publications and source records attributed to Bright, A..

2 recordsLinked to original sources

bioRxiv2026

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

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 Parkinsons 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 Parkinsons disease.

neuroscience↗

bioRxiv2025

Genome-wide CRISPR screen reveals Wnt signaling defects regulate lipid accumulation in APOE4 oligodendrocytes

APOE4 is the largest genetic risk factor for late-onset Alzheimers disease, but the cellular mechanisms by which APOE variants influence risk of disease remain incompletely understood. We have previously found that APOE4 expression led to the intracellular accumulation of lipid droplets in oligodendrocytes, causing decreased myelination. However, the mechanisms by which APOE4 alters lipid metabolism are not fully understood. Here, we leveraged a genome-wide CRISPR screen and ATAC-sequencing in human induced pluripotent stem cell (iPSC)-derived oligodendrocytes to dissect APOE4s lipid-associated mechanisms of action. Using these approaches, we identified decreased Wnt signaling, and overactive GSK3b activity, as regulators of lipid droplet accumulation in oligodendrocytes. Genetic and pharmacological inhibition of GSK3b reduced lipid droplets in APOE4 oligodendrocytes, and increased myelination in three-dimensional iPSC-derived brain organoids. Finally, we show that pharmacological inhibition of GSK3b reduces lipid droplets and improves myelination in APOE4;PS19 Tau transgenic mice. Together, our results provide a framework for understanding the mediation of APOE4-related changes to oligodendrocyte lipid metabolism and myelination.

neuroscience↗