'Primate-specific genetic variation' pathway causing dementia-related neuronal damage identified for first time

Researchers in South Korea have identified for the first time the pathway through which a genetic variation found only in primates causes dementia-related neuronal damage.

According to science news outlet Azolife Sciences on the 29th (local time), a team led by Lee Mi-ok and Dr. Miyoung Son of the Stem Cell Convergence Research Center at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) used human stem cell-derived brain organoids to uncover how Alu element-mediated gene deletion leads to neuronal damage and dementia-related neurodegeneration.

Alu elements are short DNA sequences found only in primates, including humans and monkeys, and account for approximately 10% of the human genome. Abnormal recombination between two Alu elements can delete the genetic information between them. Because mice lack Alu elements, it has been difficult to study the effects of these changes on the human brain.

The researchers focused on the SPAST gene, which is known to cause hereditary spastic paraplegia. Some patients with large deletions in the SPAST gene experience not only motor symptoms but also cognitive decline and dementia, although the cause has remained unknown.

The team created human brain organoids from stem cells carrying a deletion in SPAST exon 17, mimicking the genetic variation identified in patients. The results showed that the deleted SPAST gene abnormally connected with the adjacent SLC30A6 gene, generating a fusion transcript.

This abnormal connection reduced levels of the zinc transporter ZnT6 in the Golgi apparatus to approximately half the normal level. As ZnT6 levels fell, zinc abnormally accumulated in the cytoplasm, disrupting intracellular zinc balance and accompanying fragmentation of the Golgi apparatus, which processes and transports proteins and lipids.

These changes led to neurodegenerative abnormalities in the brain organoids. Amyloid beta aggregation, a hallmark of Alzheimer disease, increased approximately 10-fold compared with controls, while the number of apoptotic neurons increased approximately fourfold.

The researchers also tested whether intervening in the newly identified pathway could reduce neuronal damage. Reducing excess intracellular zinc with a zinc-specific chelator or preventing Golgi fragmentation restored Golgi structure and reduced amyloid beta levels. Other pathological features, including lipid abnormalities, were also alleviated.

The team also analyzed postmortem brain tissue from patients with Alzheimer disease. The analysis confirmed an association between abnormal ZnT6 expression and Golgi fragmentation in Alzheimer disease brains. In 1 of 2 patient samples suitable for RNA analysis, the researchers detected an abnormal SPAST–SLC30A6 fusion transcript of the same type identified in the brain organoid model. However, because the sample size was small, further research is needed to determine how broadly this mechanism applies to sporadic Alzheimer disease.

Dr. Lee Mi-ok said, "This study demonstrated that genetic variations arising from human-specific DNA structures disrupt zinc balance and Golgi function, ultimately causing dementia-related neurodegeneration. We hope that this newly identified association will contribute to understanding the mechanisms of dementia and other neurodegenerative diseases and to developing new treatments."

The study was published online on the 29th of last month in the international journal Signal Transduction and Targeted Therapy.