TE RNA changes in human brains during aging and neurodegenerative disorders suggest that expression of particular TE RNAs may serve as biomarkers of human brain aging and neurodegenerative disorders.
Key Findings
Results
Human brain transcriptomes from the BrainSpan Atlas display significant shifts of TE small RNA (smRNA) patterns during aging.
TE smRNA patterns showed significant shifts across human brain aging as assessed from the BrainSpan Atlas dataset.
The human frontal cortex displayed the most pronounced sense TE smRNAs among brain regions examined.
A negative relationship was observed between TE smRNAs and large RNAs (laRNAs) in the frontal cortex, indicative of age-associated regulatory effects.
Results
Aging mouse brains lack any TE RNA changes despite a clear shift in aging-associated gene messenger RNA (mRNA) levels.
Unlike human brains, aging mouse brains showed no detectable TE RNA changes.
Aging-associated gene mRNA level shifts were still clearly present in the mouse brain data.
This divergence suggests species-specific regulation of TE RNA dynamics during brain aging.
Results
Huntington's disease (HD) is characterized primarily by TE small RNA dysregulation.
HD showed a stronger impact on TE smRNAs relative to TE laRNAs.
The authors suggest this pattern may potentially correlate with the earlier average age of death for HD relative to PD.
This smRNA-dominant dysregulation pattern distinguishes HD from PD in terms of TE RNA dynamics.
Results
Parkinson's disease (PD) shows a stronger impact on TE large RNAs (laRNAs) compared to TE small RNAs.
PD displayed a more pronounced effect on TE laRNA expression compared to HD.
The differential TE RNA impact between HD and PD may reflect differences in disease onset and progression.
The authors propose this laRNA-dominant pattern potentially correlates with the later average age of death in PD relative to HD.
Results
The TE-silencing factor TRIM28 is downregulated in adult human brains.
TRIM28 downregulation was observed in adult human brain tissue.
The authors propose that TRIM28 downregulation may explain some of the observed TE RNA changes during human brain aging.
TRIM28 is described as a TE-silencing factor, implying its reduced expression could lead to derepression of TE transcription.
Methods
The study used both postmortem human and mouse brain samples to quantify TE RNA changes across aging and neurodegenerative conditions.
Human brain data were sourced from the BrainSpan Atlas.
Both TE small RNAs (smRNAs) and large RNAs (laRNAs) were tracked to assess regulatory relationships.
Neurodegenerative disorders examined included Huntington's disease (HD) and Parkinson's disease (PD).
TE smRNA tracking was used to assess the relationship to TE laRNA expression patterns as a measure of regulatory effects.
What This Means
This research suggests that certain mobile genetic elements in our DNA, called transposable elements (TEs), produce RNA molecules whose levels change in the human brain as we age and in neurodegenerative diseases like Huntington's and Parkinson's disease. The study found that the human brain undergoes significant shifts in the levels of small TE RNAs with age, and that in the frontal cortex these small RNAs appear to suppress the production of larger TE RNAs — a sign that the brain has regulatory mechanisms to keep these elements in check, though these mechanisms appear to shift with age. Notably, aging mouse brains did not show the same TE RNA changes, even though normal aging-related gene activity shifts were still present, suggesting that TE regulation during brain aging may be uniquely important in humans.
The study also found that Huntington's disease and Parkinson's disease affect TE RNA in different ways: HD primarily disrupts small TE RNAs, while PD has a stronger effect on large TE RNAs. The researchers speculate this difference may relate to the fact that HD patients tend to die at a younger age on average than PD patients. Additionally, a protein called TRIM28, which normally helps silence transposable elements, was found to be less active in adult human brains, which may help explain why TE RNA levels change with age and disease.
This research suggests that specific TE RNA molecules could potentially serve as biological markers — or biomarkers — for brain aging and neurodegenerative diseases. Understanding how these ancient genomic elements behave in the aging and diseased brain could open new avenues for studying and potentially detecting these conditions earlier, though further research is needed to translate these findings into clinical applications.
Dayama G, Lee J, Gupta S, Brion C, Connizzo B, Labadorf A, et al.. (2026). Transposable element small RNAs and large RNAs in aging brains and implications in Huntington's and Parkinson's disease.. Genome research. https://doi.org/10.1101/gr.280565.125