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.

To investigate this process, the team generated human brain organoids from stem cells engineered to carry a deletion in SPAST exon 17, mimicking a genetic alteration found in patients.

The researchers discovered that the deleted SPAST gene became abnormally connected to the neighboring SLC30A6 gene, generating a fusion transcript. This abnormal connection reduced levels of ZnT6, a zinc transporter encoded by SLC30A6 and located in the Golgi apparatus, to about half of normal levels.

As ZnT6 levels declined, zinc accumulated abnormally in the cytoplasm, disrupting intracellular zinc balance. This was accompanied by fragmentation of the Golgi apparatus, the cellular structure responsible for processing and transporting proteins and lipids.

These changes ultimately led to neurodegenerative abnormalities in the brain organoids. Amyloid-beta aggregation, a hallmark associated with Alzheimer's disease, increased by approximately 10-fold, while apoptotic neurons increased by about fourfold compared with controls.

The research team then tested whether intervening in this newly identified pathway could reduce neuronal damage.

When the researchers reduced excess intracellular zinc using a zinc-specific chelator or prevented Golgi fragmentation, Golgi structure was restored and amyloid-beta levels decreased. The interventions also alleviated lipid abnormalities and other pathological features, demonstrating the therapeutic potential of targeting the ZnT6–Golgi axis.

To examine whether the findings might also be relevant to more common forms of dementia, the team analyzed postmortem brain tissue from patients with Alzheimer's disease.

The researchers found an association between abnormal ZnT6 expression and Golgi fragmentation in Alzheimer's disease brains. In addition, among the two patient samples suitable for RNA analysis, one contained the same type of abnormal SPAST–SLC30A6 fusion transcript identified in the brain organoid model. Because the number of samples was limited, however, further research is needed to determine how broadly this mechanism applies to sporadic Alzheimer's disease.

The study is significant because it identifies a previously unknown pathway in which a primate-specific genomic alteration disrupts zinc homeostasis and Golgi function, ultimately leading to neuronal damage and dementia-related pathology.

It also demonstrates the value of human brain organoids for investigating disease mechanisms that are difficult to reproduce in conventional animal models, while providing a potential therapeutic strategy for structural variant-driven neurodegeneration.

This study demonstrates that a genetic alteration arising from a DNA structure characteristic of humans can disrupt zinc balance and Golgi function, ultimately leading to dementia-related neurodegeneration. We hope this newly identified link will contribute to a better understanding of the mechanisms underlying dementia and other neurodegenerative diseases and ultimately support the development of new therapeutic approaches."

Dr. Mi-Ok Lee, study's lead investigator

Korea Research Institute of Bioscience and Biotechnology (KRIBB) is a leading national research institute in South Korea dedicated to cutting-edge research in biotechnology and life sciences. Established in 1985, KRIBB focuses on advancing scientific knowledge in areas such as molecular biology, genomics, bioinformatics, synthetic biology, and aging-related studies. As a government-funded institute, KRIBB plays a pivotal role in driving innovation, supporting national R&D strategies, and collaborating with academic and industrial partners both domestically and internationally.
The study was published online on July 29 in Signal Transduction and Targeted Therapy (Impact Factor: 81.2), a leading international journal in translational medicine.

The article is titled "Alu-mediated SPAST deletion impairs golgi zinc transport and reveals a druggable vulnerability."

The corresponding authors are Dr. Mi-Young Son and Dr. Mi-Ok Lee of the Korea Research Institute of Bioscience and Biotechnology (KRIBB). The first authors are Youngsun Lee, Onju Ham, and Hana Lee. The English spellings follow those used in the published article.

This research was supported by the KRIBB Strategic Research Program, the Bio and Medical Technology Development Program of the Ministry of Science and ICT, the Human Organoid-Based Regenerative Therapy Technology Development Program, and the National Preclinical Trial Support System Development Program.