Primate-specific DNA change reveals a new link to dementia-related 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.
A new study reveals a link between a primate-specific DNA alteration and dementia-related neurodegeneration. Researchers from the Korea Research Institute of Bioscience and Biotechnology focused on the SPAST gene, which, when mutated, causes hereditary spastic paraplegia. However, some patients with SPAST deletions also experience cognitive decline and dementia, though the mechanism was unclear.
The team created human brain organoids with a SPAST exon 17 deletion to study the issue. They discovered that the missing SPAST gene fused with the neighboring SLC30A6 gene, decreasing ZnT6 zinc transporter expression to about half of normal levels. Zinc accumulation in the cytoplasm disrupted the Golgi apparatus, leading to neurodegenerative abnormalities.
Alzheimer's-associated amyloid-beta aggregation increased by 10-fold, and neurons increased by fourfold compared to controls. Restoring intracellular zinc levels by using a zinc-specific chelator or preventing Golgi fragmentation improved the situation, demonstrating the potential of targeting the ZnT6-Golgi axis.
The researchers found an association between abnormal ZnT6 expression and Golgi fragmentation in Alzheimer's disease brains. One patient sample had the same SPAST-SLC30A6 fusion transcript found in the organoid model. Further research is needed to determine the extent of this mechanism in sporadic Alzheimer's disease.
The study highlights a previously unknown pathway involving a primate-specific genomic alteration that disrupts zinc homeostasis and Golgi function, ultimately causing neuronal damage and dementia-related pathology. It also demonstrates the potential of human brain organoids for investigating disease mechanisms that are difficult to study in conventional animal models and suggests a therapeutic strategy for neurodegeneration caused by structural variant-driven changes.
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