Transposable elements, sometimes called “jumping genes”, are repetitive DNA sequences that can copy and insert themselves into different parts of our genome. For a long time, these elements were thought to be silent in the brain, but recent studies have indicated that they may be altered in Parkinson’s disease. Still, their broader expression across brain regions and cell types remained largely unexplored until the laboratory of Molecular Neurogenetics systematically mapped transposable element expression across multiple brain regions.
They decided to investigate the expression of transposable elements in four separate brain regions from 25 deceased Parkinson’s Disease donors, and 18 age- and sex-matched controls. But they stumbled into a problem. Since identical copies of transposable elements occur throughout the genome, tracing the origin of their activity is like finding which sheep from a flock left a particular hoofprint. The researchers tackled this challenge by developing a new analytical method to pinpoint the source and identify the cell type it came from.
We developed a novel analytical framework to detect cell-type-specific transcriptional changes of transposable elements
“We developed a novel analytical framework to detect cell-type-specific transcriptional changes of transposable elements using standard single-cell techniques,” explains Raquel Garza, postdoc and first author of the study.
The new framework revealed that rather than being silent genomic passengers, transposable elements form a diverse choir of voices across the human brain. Their analyses revealed over a thousand transposable elements expressed in a region- and cell-type-specific pattern across the human brain.
We detected changes in cellular states – specifically in microglia and medium spiny neurons – in the brain regions substantia nigra and putamen of Parkinson’s disease patients,
“We detected changes in cellular states – specifically in microglia and medium spiny neurons – in the brain regions substantia nigra and putamen of Parkinson’s disease patients,” continues Raquel Garza.
Both substantia nigra and putamen regions are central to Parkinson’s disease pathology. The altered expression included endogenous retroviruses – remnants of ancient viral infections embedded in our DNA. And the transcriptional activation coincided with an innate immune response in those same regions. So, what if inflammation and transposable element activation trigger each other?
Neuroinflammation – inflammation in the brain – in Parkinson’s disease has been recognized for decades even though its role in disease development has been debated. Not long ago, researchers assumed it was a consequence of neuronal death, but recent studies suggest that inflammation may also contribute to disease progression.
To explore this link further, Johan Jakobsson’s team turned to the cell lab. Using human stem cells, they generated microglia and dopamine-producing neurons, which they exposed to interferon molecules to mimic an inflammatory environment.
“Our cell experiments show that interferon treatment is sufficient to trigger the transcription of transposable elements,” says Raquel Garza.
Research group leader Johan Jakobsson thinks this reframes the view of neuroinflammation in Parkinson's Disease.
“This study highlights that the idea of transposable elements being silent genomic features is completely outdated. Our results suggest that neuroinflammation may also be a cause, or at least an amplifier, and that this might be driven by transposable elements,” concludes Johan Jakobsson.
If transposable elements are actively expressed in the human brain, they should no longer be masked from analyses – as they have been in the past. Recognizing their activity opens up a completely new set of questions about disease mechanisms and potential targets for future treatments.
If we can understand what is triggering this pathway, we may be able to identify ways to intervene earlier,
“If we can understand what is triggering this pathway, we may be able to identify ways to intervene earlier, before the inflammatory cascade causes irreversible damage,” ends Johan Jakobsson.
