By Michelle Jaffee
An MBI research team has discovered a molecular mechanism driving a toxic buildup of the protein tau in progressive supranuclear palsy, a rare brain disease sometimes misdiagnosed in early stages as Parkinson’s disease.
The preclinical findings, reported in The Journal of Neuroscience, point to new therapeutic targets for PSP, a debilitating disorder with no effective treatments that affects balance, swallowing and difficulty aiming one’s eyes, among other functional losses.
The new study, led by Joe Abisambra, Ph.D., used human brain tissue from PSP donors and a fruit fly model to uncover new insights into the disease process.
To begin, the team used CRISPR gene-editing technology to develop a cell model of PSP that suppressed PERK-B, a common genetic variant associated with increased risk of the disease. (A small percentage of PSP cases are considered genetic; in most cases, its origin is unknown.)
Examining the mutant cell model, the researchers found differences in four proteins; of these, only one — the DLX1 protein — has been previously associated with PSP. The researchers then confirmed this finding in human PSP brain tissue and, by reducing DLX1 levels in the fly model, observed a decrease in tau-induced toxicity.
The results unveil a previously unknown PERK-B/DLX1 pathway contributing to tau buildup, and this has implications not only for PSP but also other tau-defined diseases, said Abisambra, a UF professor of neuroscience who serves as MBI associate director of research programs.
“This study suggests that inhibiting DLX1 protein in patients could potentially help alleviate symptoms and improve their quality of life,” he said.
The next step in this line of research is to target DLX1 in mouse models to measure changes in brain function, Abisambra said. Additionally, the research team will examine the effects of three other proteins identified in the study.