Do transposons contribute to age-related neurodegeneration?
As the body ages, a number of visible changes occur, such as the appearance of wrinkles on the skin and a decrease in the ability to tolerate physical exertion. However, at the same time, less noticeable processes occur, one of which can lead to age-related disorders of the functioning of the brain.
Researchers at the Cold Spring Harbor Laboratory, working under the guidance of Associate Professor Joshua Dubnau, have demonstrated that as fruit flies age, the number and activity of so-called "jumping genes" or transposons increases in the brain of fruit flies.
Discovered in the 1940s by Professor Barbara McClintock in experiments with corn cells, transposons are repetitive DNA sequences that can be embedded in the DNA of animals and plants.
The term "jumping genes" originated from the fact that when activated, transposons can spontaneously move from one region of the genome to another. It is believed that in this way they are able to cause variations in the functioning of genes, and in the case of germ cells, to have a potentially destructive effect.
The average life expectancy of a fruit fly is 40-50 days. However, these insects are a valuable model for studying the genetics of processes such as aging and brain functioning, including memory mechanisms.
The authors' interest in transposons was caused by the results of the experiment, which showed that a decrease in the activity of the Ago2 protein (Argonaute 2) worsened long-term memory, the ability to form which was assessed using the classical, according to Pavlov, conditioned reflex – reaction to smell. According to Dabnau, this neurodegenerative effect is significantly aggravated in aging fruit flies.
The participation of the Ago2 protein in ensuring the protection of the drosophila genome from the activity of transposons led scientists to the idea of the need to clarify the role of "jumping genes" in this phenomenon.
Despite the fact that the activity of transposons is observed during the normal development of the brain, in the future they go into a passive state. This indicates that they have a certain functional role in development.
Observation of the behavior of transposons in the brain of adult fruit flies revealed a significant increase in their activity in neurons starting from the age of 21 days. As the organism aged further, their activity steadily increased, which was manifested by frequent movements within the genome. The transposon known as gypsy (gypsy in English, so its discoverers clearly did not suffer from a lack of a sense of humor) turned out to be especially active.
Blocking the activity of the Ago2 gene led to the activation of transposons in the drosophila brain at a much earlier age. This was manifested by the lack of long-term memory in such individuals already at the age of 20 days, which is not typical for normal insects.
Collage by Joshua Dabnau: on a portrait of a fruit fly obtained using a scanning electron microscope,
the eyes are tinted and the image of fluorescent labels is superimposed,
showing the localization of active transposons in the brain.
In earlier work, the authors demonstrated the existence of a relationship between transposon activity and severe neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. This relationship is mediated by the protein TDP-43, which controls the activity of transposons.
Comparing these data with the results of a new study, Dabnau suggests that the cause of age-related neurodegeneration, as well as disorders observed in a number of neurodegenerative diseases, may be a kind of "transposon storm".
However, within the framework of the conducted studies, it has not been established whether transposons are the cause or consequence of age-related brain disorders. The next stage of the scientists' work will be an attempt to activate transposons through genetic manipulation of fruit flies to get an answer to the question: are they the direct cause of neurodegeneration.
Article by Wanhe Li et al. Activation of transposable elements during aging and neuronal decline in Drosophila is published in the journal Nature Neuroscience.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Cold Spring Harbor Laboratory:
CSHL neuroscientists show ’jumping genes’ may contribute to aging-related brain defects.
09.04.2013