By inserting an amyotrophic lateral sclerosis (ALS)-linked human gene called TDP-43 into fruit flies, researchers have discovered a potential role for ‘transposons’ in the disease. Transposons, which are also called ‘jumping genes’ because they jump from place to place within DNA, are virus-like entities that fill most of the spaces between genes in an organism. The new research demonstrates that these transposons are no longer effectively inhibited, resulting in a storm of jumping genes, leading to DNA damage accumulation and cell death. The research, published in PLOS Genetics, may be a clue to the genetic processes of ALS and the idea that anti-transposon systems may collapse in individuals with ALS.
Transposon replication has evolved to the point where almost half of human DNA consists of these jumping gene sequences. But our cells have developed a highly effective immune-like system to stifle the replication of these moving genes in a vast majority of instances. The researchers conducted experiments using transgenic fruit flies and discovered that anti-transposon systems appear to collapse in brains of fruit flies that contain the ALS linked human gene.
In the study, the researchers engineered the fruit flies to contain TDP-43. Just like humans, this gene caused the fruit flies to experience a progressive loss of movement and premature death. Studying the brains of the fruit flies, the team found that not only were certain transposons not inhibited and triggered a storm of the jumping genes, but one fly transposon called ‘gypsy’ appeared to be the lead culprit of the problem. By deactivating gypsy, cell death stopped and the lifespan of the mutant flies improved.
Humans do not have the gypsy transposon but do have a similar one called HERV-K. Previous research has revealed some ALS patients post-mortem had elevated levels of HERV-K.
The next step for the research team is to determine whether jumping genes are similarly activated in ALS patient tissue, and to determine whether they contribute to disease progression.
Paper “Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS”
Reprinted from materials provided by Stony Brook University.