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How Hidden Genetic Elements Trigger a Rare Neurodegenerative Disorder

Stock image of DNA
Researchers at Lund University have discovered how a hidden piece of DNA, known as a transposable element, disrupts normal gene function in a disease called X-Linked Dystonia-Parkinsonism (XDP). Image // Science Photo Library

Researchers at Lund University have discovered how a hidden piece of DNA, known as a transposable element, disrupts normal gene function in a disease called X-Linked Dystonia-Parkinsonism (XDP). Published in Nature Structural and Molecular Biology, their findings uncover the epigenetic processes that lead to changes in gene expression linked to XDP, offering new insights into how this rare genetic condition is triggered in adulthood.

X-Linked Dystonia-Parkinsonism (XDP) is an inherited disorder that primarily affects men with Filipino ancestry from Panay Island. The condition, which causes movement problems such as dystonia and parkinsonism, begins in adulthood. Patients experience everything from muscle cramps to slow movements, tremors, stiffness, and difficulties in daily activities like walking and speaking.

Earlier research in the field identified the insertion of a transposable element in the TAF1 gene as the cause of XDP. These transposable elements, also known as transposons or jumping genes, are DNA segments that can move around the genome and contribute to genetic diversity as they can be passed down through generations.

Vivien Horvath, a postdoctoral researcher in the Laboratory of Molecular Neurogenetics and first author of the study, explains, "Studies indicate that there may be a new transposon mobilization in one out of every twenty births, introducing unique genetic variations in the population." While they can contribute to genetic diversity, transposable elements can also cause diseases like XDP by inserting themselves into important genes and disrupting their function.

"Our goal was to understand how the insertion of the XDP-specific transposon affects the TAF1 gene and leads to the disease," notes Vivien. The study used neural stem cells obtained from patients with XDP and their healthy relatives. This approach provided a human cellular model closely mimicking patient conditions, allowing the team to observe the effects of epigenetic regulation in a relevant biological context.

"Our findings offer new insights into transposon control and their regulatory effects in the context of disease development," elaborates Vivien. “The insights gained provide a roadmap for future research into how our genes can be affected by these hidden elements, ultimately leading to different disorders.”

Image with the TAF1 gene schematic
Illustration comparing the TAF1 gene in a healthy individual and in a patient with XDP. The SVA retrotransposon, highlighted in red, has been associated with the disease and is inserted in the 32nd intron of the TAF1 gene.

Using advanced techniques – CRISPRi, CUT&RUN, and Oxford Nanopore Sequencing- to modify gene expression and to look at long DNA sequences, researchers explored the repressive epigenetic mechanisms controlling transposons. They found that this epigenetic defense system recognizes the XDP transposon and also protects the TAF1 gene from its effect. 

The study highlighted ZNF91, a protein important in regulating insertions similar to the one in XDP. This protein places special chemical tags, known as repressive epigenetic marks, like histone methylation and DNA methylation, around the transposon in the TAF1 gene. "When we removed these epigenetic marks, the misregulation of the TAF1 gene worsened. Based on these results we hypothesize that maintaining these marks is crucial for normal TAF1 gene expression," Vivien emphasizes.

Their findings suggest that changes or loss of these epigenetic marks during aging might be responsible for the adult onset of XDP symptoms.  “What we think happens is that for the first part of a patient's life, that gene region is protected. Later, as these epigenetic marks change, the region is no longer protected, leading to the misregulation of gene expression,” explains Vivien.

Looking ahead, these findings could lead to new treatments. "One exciting possibility is developing a DNA methylation replacement therapy," says Vivien. "By maintaining these protective epigenetic marks throughout life, we may be able to prevent the onset or progression of XDP. But there is still much to learn before we get to that point."

Key Terms:

To help you better understand the study mentioned above, here are some key concepts explained:

Transposable Elements (Transposons):

  • What They Are: Segments of DNA that can make new copies of themselves and insert these copies into the genome.
  • How They Work: These elements can make copies of themselves that "jump" to new positions, potentially disrupting normal gene function or creating new genetic variations.
  • Why They Matter: While they can contribute to genetic diversity, transposable elements can also cause diseases like XDP by inserting themselves into important genes and disrupting their function.

CRISPRi (CRISPR Interference):

  • What It Is: A technique that uses a modified version of the CRISPR-Cas9 system to block the expression of specific genes without cutting the DNA.
  • How It Works: By targeting specific genes, CRISPRi can effectively "turn off" these genes, allowing scientists to study their function by observing what happens when they are inactive.
  • Why It Matters: This tool helps researchers understand the role of specific genes in diseases like X-Linked Dystonia-Parkinsonism (XDP).

CUT&RUN (Cleavage Under Targets and Release Using Nuclease):

  • What It Is: A method used to identify the binding sites of DNA-associated proteins within the genome.
  • How It Works: It uses an enzyme to cut DNA at points where proteins are bound, releasing the DNA fragments for analysis.
  • Why It Matters: This technique allows scientists to map where and how proteins interact with DNA, providing insights into gene regulation.

Oxford Nanopore Long-Read Sequencing:

  • What It Is: An advanced sequencing technology that reads long sequences of DNA or RNA in real-time.
  • How It Works: DNA strands pass through tiny pores (nanopores), and the sequence of bases (A, T, C, G) is determined by measuring changes in electrical current as each base passes through.
  • Why It Matters: Long-read sequencing provides a more comprehensive view of genetic regions, especially those with complex structures such as transposable elements, enhancing our understanding of genetic disorders.

These innovative techniques and concepts are key in advancing our understanding of genetic diseases and developing potential new treatments.


Photo of Vivien H.

Vivien Horvath is a postdoctoral researcher in the Laboratory of Molecular Neurogenetics. 

Profile in the Lund University Research Portal

Portrait of Johan Jakobsson. Photo.

Johan Jakobsson is a Professor within the Faculty of Medicine at Lund University and leads the Laboratory for Molecular Neurogenetics which is affiliated with Lund Stem Cell Center and MultiPark.

Profile in Lund University Research Portal


Horváth, V., Garza, R., Jönsson, M.E. et al. Mini-heterochromatin domains constrain the cis-regulatory impact of SVA transposons in human brain development and disease. Nature Structural and Molecular Biology (2024).

Transposable Elements/ XDP/ DNA methylation

The work was supported by grants from the Collaborative Center for X-Linked Dystonia-Parkinsonism, the Swedish Research Council, the Swedish Brain Foundation, Cancerfonden, Barncancerfonden, the Swedish Society for Medical Research, and the Swedish Government Initiative for Strategic Research Areas (MultiPark & StemTherapy).