Primate-Specific DNA Change Linked to Dementia-Related Brain Damage, Study Finds

Scientists at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) have identified a genetic pathway that may be linked to dementia-related brain cell damage, using lab-grown human brain tissue rather than mice. The peer-reviewed study, led by Dr. Mi-Ok Lee and Dr. Mi-Young Son, was published in the journal Signal Transduction and Targeted Therapy.

The team studied Alu elements, short DNA sequences making up about 10% of the human genome that exist only in primates, including humans and monkeys. Mice lack Alu elements, so it has been hard to study how abnormal rearrangements of these sequences affect the human brain. The researchers focused on the SPAST gene, where mutations cause hereditary spastic paraplegia, a disorder marked by leg stiffness and weakness. Some patients with large SPAST deletions also develop cognitive decline and dementia, for reasons that had remained unclear.

To investigate, the team grew human brain organoids, small lab-grown clusters of brain-like tissue from stem cells, carrying patients' SPAST deletion. The deleted gene became abnormally joined to a neighboring gene, SLC30A6, forming a fusion transcript that cut production of ZnT6, a zinc-transport protein in the Golgi apparatus, a structure that processes proteins, to about half its usual level. Zinc built up abnormally inside the cells and the Golgi apparatus fragmented. This was associated with about a tenfold rise in clumps of amyloid-beta, a protein linked to Alzheimer's disease, and about four times more dying neurons than in controls.

Lowering the excess zinc, or blocking the Golgi fragmentation, restored Golgi structure and reduced amyloid-beta levels, suggesting a possible drug target. Examining postmortem brain tissue from Alzheimer's patients, the team found abnormal ZnT6 activity was associated with Golgi fragmentation, and one of two testable samples carried the same SPAST-SLC30A6 fusion seen in the organoids. Because only a small number of samples could be analyzed, the researchers said more research is needed to see how broadly the pathway applies to Alzheimer's disease.