Human organoids link Alu-mediated DNA deletion to neuronal damage

Inside human brain organoids, a tiny change in DNA produced a large cellular disturbance. Researchers led by Dr. Mi-Ok Lee and Dr. Mi-Young Son at South Korea's Korea Research Institute of Bioscience and Biotechnology modeled a patient-linked deletion in exon 17 of the SPAST gene and found that amyloid-beta aggregation rose by approximately 10-fold compared with controls.

The clue lies in Alu elements, short DNA sequences found in primates, including humans and monkeys, that make up approximately 10% of the human genome. Abnormal recombination between them can remove the DNA between two elements. Mice do not carry Alu elements, making this kind of human genetic event difficult to study in conventional animal models.

In the engineered organoids, the damaged SPAST gene became abnormally connected to its neighbor, SLC30A6, creating a fusion transcript. That reduced ZnT6, a zinc transporter in the Golgi apparatus—the cell structure that processes and moves proteins and lipids—to about half of normal levels. Zinc then accumulated abnormally in the cell's cytoplasm, while the Golgi fragmented. Apoptotic neurons increased by about fourfold.

The team could ease several of these changes. A zinc-specific chelator reduced excess intracellular zinc, while another intervention prevented Golgi fragmentation; both restored Golgi structure and lowered amyloid-beta levels, alongside improvements in lipid abnormalities and other pathological features. The experiments identify the ZnT6–Golgi axis as a possible treatment target, but they remain laboratory results from organoids.

And so what, concretely? The model gives researchers a way to test therapies for a genetic form of neurodegeneration that mice cannot reproduce well because they lack Alu elements. The team also found an association between abnormal ZnT6 expression and Golgi fragmentation in Alzheimer's disease brain tissue. However, only two patient samples were suitable for RNA analysis, and only one carried the same fusion transcript, so the relevance to sporadic Alzheimer's disease still needs broader testing.