Transposable DNA elements yield new clues to origins of neurodegenerative disease

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"For the new study, the ... team ... — explored the role of one the most common transposable elements, known as long interspersed nuclear element 1 (LINE-1), in neurodegenerative disease.

They found that activation of LINE-1 correlated with damage to the cerebellum in patients with ataxia-telangiectasia, a rare condition that impairs coordination and causes deficits in immune and other body systems. LINE-1 elevation in the cerebellum of these patients was associated with significant neuroinflammation, they found. The median life expectancy of patients with the disorder is between 19 and 25 years of age.

In mouse models of the disorder, researchers found that the activation of LINE-1 was sufficient to cause cellular damage and death in the cerebellum of mice. However, when the mice were treated with reverse transcriptase inhibitors — such as the ones used in treatment of HIV —progression of the disorder was reduced. ...
The findings are intriguing, researchers said, because several different labs are now exploring the role of LINE-1 in onset of neurodegenerative diseases such as schizophrenia, Amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease. ..."

From the abstract:

"Dysregulation of long interspersed nuclear element 1 (LINE-1, L1), a dominant class of transposable elements in the human genome, has been linked to neurodegenerative diseases, but whether elevated L1 expression is sufficient to cause neurodegeneration has not been directly tested. Here, we show that the cerebellar expression of L1 is significantly elevated in ataxia telangiectasia patients and strongly anti-correlated with the expression of epigenetic silencers. To examine the role of L1 in the disease etiology, we developed an approach for direct targeting of the L1 promoter for overexpression in mice. We demonstrated that L1 activation in the cerebellum led to Purkinje cell dysfunctions and degeneration and was sufficient to cause ataxia. Treatment with a nucleoside reverse transcriptase inhibitor blunted ataxia progression by reducing DNA damage, attenuating gliosis, and reversing deficits of molecular regulators for calcium homeostasis in Purkinje cells. Our study provides the first direct evidence that L1 activation can drive neurodegeneration."

‘Jumping’ genes yield new clues to origins of neurodegenerative disease | YaleNews

LINE-1 activation in the cerebellum drives ataxia (open access)