“Jumping Genes” Trigger Inflammation in Alzheimer’s
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Researchers from The University of Texas San Antonio have identified a molecular process that leads to abnormal RNA production in Alzheimer’s disease and a rare brain disorder, progressive supranuclear palsy. The abnormal RNA behaves similarly to inflammatory triggers in viral infections. The study is published in Science Advances.
Tau drives neuroinflammation – but how?
Alzheimer’s disease and progressive supranuclear palsy are both characterized by a toxic buildup of tau protein aggregates, which can negatively affect genomic and cellular architecture. Tau can induce so-called “jumping genes” to copy themselves to new areas of the genome.
Transposable elements – also called jumping genes – are lengths of DNA usually between 100 to 10,000 base pairs long, which can replicate themselves within the genome. They are classified into two groups; retrotransposons, which “copy and paste” to replicate via an RNA intermediate, and DNA transposons, which “cut and paste” for the element itself to move to a different location in the genome.
The new research suggests that as tau-induced retrotransposons move around the genome, they behave similarly to retroviruses, forming a double-stranded RNA intermediate and driving neuroinflammation.
Transposable elements: A new area of interest
“Transposable elements are a new area of interest in understanding Alzheimer’s disease. Our study provides new insights into how they can drive the disease process in addition to their ability to jump,” said Dr. Elizabeth Ochoa, author of the new study. “These double-stranded RNAs look like a virus to the immune system even though the jumping genes are a part of our normal genome.
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“We found substantial deposits of double-stranded RNA in astrocytes, which are cells that provide metabolic support for neurons, regulate neurotransmitters and maintain blood-brain barrier integrity,” said Dr. Bess Frost, senior author of the paper. “In aging and disease, astrocytes respond to injury and disruption of the neuronal environment. Our findings open new doors for understanding astrocyte biology and their role in transposable element control.”
“As we are currently targeting jumping gene activation in a local Phase II clinical trial for patients with Alzheimer’s disease, it’s important to understand the full repertoire of toxic molecules, including double-stranded RNAs, that jumping genes produce,” she continued.
Reference: Ochoa E, Ramirez P, Gonzalez E, et al. Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation. Sci Adv. 2023;9(1):eabq5423. doi: 10.1126/sciadv.abq5423
This article is a rework of a press release from The University of Texas, San Antonio. Material has been edited for length and content.