Retrotransposon activity could be one cause of the movement disorder ataxia, a study published on September 6 in Neuron suggests. These so-called jumping genes have the ability to create copies of themselves, which then insert in new places in the genome, potentially altering genes or gene expression. The researchers found that overactivating retrotransposons called LINE-1 elements in the cerebellums of mice gave the animals problems with movement and other symptoms of ataxia, a disorder that affects balance and speech in humans. The team also found increased activity of these retrotransposons in the cerebella of patients with an inherited form of the condition.
This research “is adding to the idea of a really important role of LINE-1 in neurodegenerative diseases. And not only as a bystander, but as a potential driver,” says Julia Fuchs, a physician researcher at the College de France who studies the pathophysiology of transposable elements in the brain but who was not involved in the research. Furthermore, she says the study represents a “great moving forward in terms of what’s possible to study,” adding that further research into the underlying mechanism could reveal novel therapeutic targets.
The researchers didn’t set out to study neurodegeneration. Takehiro Takahashi, a physician at Yale School of Medicine and first author of the study, originally wanted to investigate how LINE-1 jumping affects autoimmunity, as these elements account for nearly a fifth of the human genome and are known to move about. But when Takahashi attempted to create a murine model system that allowed for targeted activation of LINE-1s in specific tissues, something unexpected happened. Mice with what should have been inactive transgenes containing a LINE-1 element “were not walking straight,” he says. It turned out that the animals’ cerebellar Purkinje neurons—brain cells with many dendrites that integrate large amounts of information—were essentially ignoring a stop sequence in the transgene, and therefore had active LINE-1s in the absence of the tissue-specific activator. “I immediately knew that this phenotype is ataxia, a motor coordination deficit,” Takahashi recalls.
Further studies on the animals revealed that the ataxia worsened over time and was accompanied by neurodegeneration in the cerebellum. Indeed, the jumping genes seemed to cause all sorts of chaos in the brain, including DNA damage, neuroinflammation, cytosolic DNA accumulation, and electrophysiological abnormalities, any or all of which could contribute to the observed neurodegeneration.
The researchers also analyzed postmortem cerebellum samples from patients with an inherited form of ataxia called ataxia telangiectasia and found that LINE-1 expression was higher in them than in matched controls, suggesting that retrotransposon activity could be a factor in the human condition.
Finally, the researchers investigated whether silencing LINE-1 elements would improve mice’s ataxia. To stop LINE-1 jumping, they gave 4-week-old model mice 3TC, an FDA-approved antiretroviral drug that blocks LINE-1 replication and is already being explored in clinical trials for treating neurodegenerative diseases. While the drug did slow the progression of the animals’ deterioration, it didn’t reverse their ataxia-like symptoms, says Takahashi.
“There is really interesting evidence for a direct causal effect of LINE-1 in neurodegeneration” in this study, says Fuchs. However, she asks “which of the downstream consequences is really the degeneration triggering part? Is it really all of these consequences together leading to degeneration, or is it one of the components more than the others. . . . And how can you act therapeutically against this?” Fuchs points out other limitations as well, such as a potential lack of specificity of the antiretroviral drugs used.
Johan Jakobsson, a molecular neurogeneticist at Lund University in Sweden who was not involved in the study, cautions that “the link to human disease really needs a lot of research,” adding that “we need to do more studies in the same line to fully understand the consequences of LINE-1 activation, and also the mechanism.” Jakobsson would also like to see the use of long-read RNA sequencing when analyzing patients’ brain samples, to be sure that LINE-1 elements are correctly quantified.
For his part, Takahashi says he’ll leave the deeper exploration of retrotransposons and neurodegeneration to others, while he returns to his initial question of how LINE-1 activation affects autoimmune disease. He’s currently working to understand the unexpected cerebellar expression in the transgenic mice and resolve it.