Primate-specific DNA change reveals a new link to dementia-related neurodegeneration

by National Research Council of Science and Technology

edited by Gaby Clark, reviewed by Robert Egan

Gaby Clark

Scientific Editor

Meet our editorial team
Behind our editorial process

Robert Egan

Senior Editor

Meet our editorial team
Behind our editorial process Editors' notes

This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

trusted source

proofread

The GIST Add as preferred source

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) 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 paper is published in the journal Signal Transduction and Targeted Therapy.

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.

A fusion transcript disrupts zinc transport

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.

Blocking the pathway eased damage

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.

Hints of the same mechanism in Alzheimer's

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.

Organoids reveal a primate-specific pathway

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," Lee said. "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."

More information

Youngsun Lee et al, Alu-mediated SPAST deletion impairs golgi zinc transport and reveals a druggable vulnerability, Signal Transduction and Targeted Therapy (2026). DOI: 10.1038/s41392-026-02785-3

Clinical categories

NeurologyClinical genetics Provided by National Research Council of Science and Technology Who's behind this story?

Gaby Clark

MA in English, copy editor since 2021 with experience in higher education and health content. Dedicated to trustworthy science news. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

Citation: Primate-specific DNA change reveals a new link to dementia-related neurodegeneration (2026, August 27) retrieved 28 August 2026 from https://medicalxpress.com/news/2026-08-primate-specific-dna-reveals-link.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.