Primate-specific Alu-mediated SPAST deletion reveals a druggable zinc–Golgi pathway in dementia-related neurodegeneration
核心洞察
Researchers at KRIBB used human brain organoids to show that an Alu-mediated SPAST (搜索) gene deletion drives dementia (搜索)-related neurodegeneration through disrupted zinc homeostasis and Golgi fragmentation.
The deletion fuses SPAST (搜索) to the neighboring SLC30A6 (搜索) gene, halving ZnT6 (搜索) zinc-transporter levels and causing roughly 10-fold amyloid-beta aggregation and fourfold apoptotic-neuron increases.
Targeting the ZnT6 (搜索)–Golgi axis with a zinc chelator or by preventing Golgi fragmentation restored Golgi structure and reduced amyloid-beta, indicating therapeutic potential.
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) (搜索) has identified a previously unknown, primate-specific pathway linking an Alu-mediated gene deletion to neuronal damage and dementia (搜索)-related neurodegeneration. Using human stem cell-derived brain organoids, the researchers demonstrated that a deletion in the SPAST (搜索) gene disrupts intracellular zinc balance and Golgi function, ultimately producing hallmark features of Alzheimer's disease (搜索) pathology.
The study, published online on July 29 in Signal Transduction and Targeted Therapy (Impact Factor: 81.2), is titled "Alu-mediated SPAST (搜索) deletion impairs golgi zinc transport and reveals a druggable vulnerability." The corresponding authors are Dr. Mi-Young Son and Dr. Mi-Ok Lee, and the first authors are Youngsun Lee, Onju Ham, and Hana Lee.
A primate-specific genomic mechanism
The work addresses a longstanding limitation in neurodegeneration research: conventional animal models such as mice cannot fully recapitulate certain human disease mechanisms. A key 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.
The researchers focused on the SPAST (搜索) gene, whose mutations are known to cause hereditary spastic paraplegia (搜索), 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 (搜索), although the mechanism behind this difference had remained unclear.
From fusion transcript to zinc dysregulation
To investigate this process, the team generated human brain organoids from stem cells engineered to carry a deletion in SPAST (搜索) exon 17, mimicking a genetic alteration found in patients. They discovered that the deleted SPAST gene became abnormally connected to the neighboring SLC30A6 (搜索) gene, generating a fusion transcript. This abnormal connection reduced levels of ZnT6 (搜索), a zinc transporter encoded by SLC30A6 and located in the Golgi apparatus, to about half of normal levels.
As ZnT6 (搜索) 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 (搜索), increased by approximately 10-fold, while apoptotic neurons increased by about fourfold compared with controls.
A druggable vulnerability
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 (搜索)–Golgi axis.
To examine whether the findings might also be relevant to more common forms of dementia (搜索), the team analyzed postmortem brain tissue from patients with Alzheimer's disease (搜索). The researchers found an association between abnormal ZnT6 (搜索) 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 (搜索)–SLC30A6 (搜索) 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.
Significance and outlook
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 (搜索)-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 (搜索)-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," said Dr. Mi-Ok Lee, the study's lead investigator.
The 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.