Brain organoids reveal how Alu-mediated gene deletion can lead to neurodegeneration

Brain diseases, including dementia, have long been studied using experimental animals such as mice. However, differences between the human and animal genomes have raised concerns that some disease mechanisms may not be fully explained by conventional animal models.

One major difference lies in Alu elements, short DNA sequences found only in primates, including humans and monkeys. Alu elements account for approximately 10% of the human genome, and abnormal recombination between them can delete genetic information located between the two elements. Because mice do not carry Alu elements, studying how such changes affect the human brain has been difficult.

A joint research team led by Dr. Mi-Ok Lee and Dr. Mi-Young Son at the Stem Cell Convergence Research Center of the Korea Research Institute of Bioscience and Biotechnology (KRIBB) has used human stem cell-derived brain organoids to uncover how an Alu-mediated gene deletion can lead to neuronal damage and dementia-related neurodegeneration.

The researchers focused on the SPAST gene. Mutations in SPAST are known to cause hereditary spastic paraplegia, a neurological disorder characterized by stiffness and weakness of the legs. Notably, some patients with large deletions in the SPAST gene develop not only motor symptoms but also cognitive decline and dementia, although the mechanism behind this difference has remained unclear.