A team at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) has used human stem cell-derived brain organoids to trace how a particular kind of genetic deletion damages neurons and drives dementia-related neurodegeneration. The work, led by Dr. Mi-Ok Lee and Dr. Mi-Young Son at KRIBB's Stem Cell Convergence Research Center, centers on Alu elements - short stretches of DNA found only in primates that make up roughly 10 percent of the human genome. When two Alu elements recombine abnormally, the genetic material sitting between them can be deleted entirely.
The gene in question is SPAST. Mutations in SPAST cause hereditary spastic paraplegia, a disorder marked by stiffness and weakness in the legs. Some patients carrying large SPAST deletions, however, go on to develop cognitive decline and dementia alongside the motor symptoms, and why that subset fares differently has not been understood.
The methodological point matters as much as the genetics. Mice, the workhorse of dementia research for decades, do not carry Alu elements at all, which means an entire class of human mutation mechanisms simply cannot occur in the standard animal model. Organoids grown from human stem cells sidestep that mismatch by keeping the human genome, and its Alu sequences, intact.
For families affected by SPAST-related disease, the finding begins to explain why some deletions produce cognitive symptoms and others do not. More broadly, it suggests that Alu-mediated deletions deserve a closer look across neurodegenerative conditions where animal models have left gaps in the explanation.