Researchers at Washington University School of Medicine in St. Louis have found a new druggable pathway that potentially could be used to help prevent Alzheimer’s dementia.
Amyloid beta accumulation in the brain is the first step in the development of Alzheimer’s dementia. Scientists have poured countless hours and millions of dollars into finding ways to clear amyloid away before cognitive symptoms arise, with largely disappointing results.
In this study, published Aug. 24 in the journal Brain, researchers found a way to increase clearance of waste products from the brains of mice by ramping up a genetic quirk known as readthrough. This same strategy also may be effective for other neurodegenerative diseases characterized by the buildup of toxic proteins, such as Parkinson’s disease, the researchers said.
Every once in a while, the brain protein aquaporin 4 is synthesized with an extra little tail on the end. At first, Darshan Sapkota, PhD — who led this study while a postdoctoral researcher at Washington University but is now an assistant professor of biological sciences at the University of Texas, Dallas — thought this tail represented nothing more than an occasional failure of quality control in the protein-manufacturing process.
“We were studying this very wonky basic science question — ‘How do proteins get made?’ — and we noticed this funny thing,” said senior author Joseph D. Dougherty, PhD, a Washington University professor of genetics and of psychiatry, and Sapkota’s former mentor. “Sometimes the protein-synthesizing machinery blew right through the stop sign at the end and made this extra bit on the end of aquaporin 4. At first, we thought it couldn’t possibly be relevant. But then we looked at the gene sequence, and it was conserved across species. And it had this really striking pattern in the brain: It was only in structures that are important for waste clearance. So that’s when we got excited.”
Scientists already knew that the cell’s protein-building machinery occasionally fails to stop where it should. When the machinery doesn’t stop — a phenomenon known as readthrough — it creates extended forms of proteins that sometimes function differently than the regular forms.
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